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10 April 2021

Recent Progress in Discovering the Role of Carotenoids and Their Metabolites in Prostatic Physiology and Pathology with a Focus on Prostate Cancer—A Review—Part I: Molecular Mechanisms of Carotenoid Action

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Medical Biochemistry Medical College, Jagiellonian University, 31-034 Cracow, Poland
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Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653 Beer Sheva, Israel
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Department of Microbiology and Immunology, Brody Medical Sciences Building, East Carolina University, Greenville, NC 27834, USA
4
Nutrition and Health Research Group, Department of Population Health, Luxembourg Institute of Health, 1 A-B, rue Thomas Edison, L-23 1445 Strassen, Luxembourg
Antioxidants2021, 10(4), 585;https://doi.org/10.3390/antiox10040585
This article belongs to the Special Issue Carotenoids, Oxidative Stress and Disease
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Abstract

Among the vast variety of plant-derived phytochemicals, the group of carotenoids has continuously been investigated in order to optimize their potential application in the area of dietary intervention and medicine. One organ which has been especially targeted in many of these studies and clinical trials is the human prostate. Without doubt, carotenoids (and their endogenous derivatives—retinoids and other apo-carotenoids) are involved in intra- and intercellular signaling, cell growth and differentiation of prostate tissue. Due to the accumulation of new data on the role of different carotenoids such as lycopene (LC) and β-carotene (BC) in prostatic physiology and pathology, the present review aims to cover the past ten years of research in this area. Data from experimental studies are presented in the first part of the review, while epidemiological studies are disclosed and discussed in the second part. The objective of this compilation is to emphasize the present state of knowledge regarding the most potent molecular targets of carotenoids and their main metabolites, as well as to propose promising carotenoid agents for the prevention and treatment of prostatic diseases.

1. Introduction

Our knowledge of the role of carotenoids in prostate biology and health has been exponentially growing during the last decades since the first investigations on BC about forty years ago [1]. Despite the increasing amount of data, we still lack not only recommendations for intake of these plant bioactives, but also thorough insight regarding the pathways that are most implicated in the proposed health benefits of carotenoids. This is true particularly for the development of prostate cancer (PC), the most concerning the disease of the prostate in contemporary medicine, although carotenoids have been implicated in other types of cancer such as of the lung [2] and several cardiometabolic diseases [3].
Carotenoids are a fairly diverse group of molecules, derived from many different plant-based food items (tomatoes, carrots, papayas, guavas, watermelons, grapes [4]), as well as some types of fungi and bacteria. Structural and functional similarity exists to retinoids and apo-carotenoids, which are often included in the classification of carotenoids. However, each of these carotenoids presents its own chemical and biological properties, which indicates the need for a separative discussion.
The last decade of studies has shown that our previous view on carotenoids did not entail all the significant aspects. Factors that were not assessed in previous trials, such as the variability of their serum levels (depending on the season), turned out to have strong effects on the outcome. Thus, the latest trials present a paradigm shift in the methodology of the evaluation and standardization of carotenoid-associated health results. A similar revolution has occurred in experimental sciences, which have started to include more sophisticated biological investigations, including microarray analysis, to precisely identify the most potent effectors of carotenoid activity at the molecular level.
These aforementioned issues have inspired us to gather data from the studies investigating the relation between carotenoids and prostate health and to present a comprehensive analysis of their biological activity in this respect. In total, 126 articles have been reviewed—including experimental and epidemiological research—to find answers to the prominent key questions: How do carotenoids modify prostate cell biology? What are the most important biological factors that contribute to the observed in vivo effects of different carotenoids? Which source of carotenoids might be the most promising for the potential treatment of PC?

2. Materials and Methods

2.1. Search Strategy and Study Selection

We have investigated electronic databases (PubMed, Cochrane, Ovid, National Institute for Health and Clinical Excellence (NICE)).
We decided to extract data between the 1st of January 2009 and 15 November 2020. The following keywords were used for the search: (carotenoids OR lycopene OR carotene OR retinoids OR retinol OR “retinoic acid” OR cryptoxanthin OR astaxanthin OR zeaxanthin OR lutein OR ionone) AND (prostate OR “prostate cancer” OR “prostate carcinoma” OR “prostate physiology” OR “prostate pathology”). The main eligibility criteria were: (a) study investigating the impact of any carotenoid or their metabolites on aspects of prostate physiology and/or pathology; (b) work not being a meta-analysis, review, editorial, comment or duplicate; (c) work published in English.

2.2. Data Extraction

The articles were investigated in detail to extract the following data: author, year, evaluated compounds and their concentrations/doses, using cell lines or animal model, quantitative or qualitative results; only results based on carotenoid concentrations (and their metabolites) ≤50 µM were considered, as higher concentrations are clearly never achievable in vivo, even when using pharmacological doses.
The flow chart summarizing the process of data extraction is presented as Figure S1 in Online Supplementary Material.

3. Carotenoids—Basic Information

Carotenoids are a group of >1100 pigments synthesized by plants, algae, some types of fungi, and photosynthetic bacteria (Table 1) [5]. Widely distributed in nature, they are responsible for the orange-red color of fruits and vegetables such as tomatoes, oranges and carrots, and the yellow color of various flowers. Carotenoids are present in photosynthetic organelles of all higher plants, mosses, ferns, and algae—they absorb light energy for their use in photosynthesis, and they protect chlorophyll from photodamage [6].
Table 1. Overview of carotenoids found in the diet.
Most carotenoids are 40-carbon terpenoids, with isoprene being their basic structural unit. They can be divided into two main classes: carotenes and xanthophylls. Carotenes contain no oxygen and are unsaturated hydrocarbons. Xanthophylls are yellow pigments with oxygen atoms present in their molecules, e.g., in form of hydroxyl groups [7]. About 50 carotenoids are present in the human diet, while only about 20 can be traced in human blood and tissues [8]. Carotenoids can also be divided according to their provitamin A activity: only those containing a β-ionone moiety can be converted to retinol [9]. The most abundant provitamin A carotenoids are BC, α-carotene and β-cryptoxanthin [10]. The efficiency of their cleavage into vitamin A (VA) is expressed by retinol activity equivalent (RAE) ratios. For example, as 12 µg of BC can be converted into 1 µg of retinol, the RAE ratio for BC equals 12:1.
There are two main enzymes engaged in the metabolism of carotenoids within the enterocytes (Figure 1): β-carotene 15, 15′-oxygenase 1 (BCO1) and BC 9′, 10′-oxygenase 2 (BCO2). BCO1 catalyzes the cleavage of provitamin A carotenoids into the retinal. Retinal is then reduced to retinol (VA) or oxidized to all-trans-retinoic acid (ATRA). BCO2 can convert provitamin A carotenoids to apo-carotenoids, however, it has a higher affinity towards non-provitamin A carotenoids. For example, BCO2 converts LC to apo-lycopenal [5]. Major proposed physiological functions of carotenoids in humans include:
Figure 1. Main metabolic pathway of carotenoids. (A) The structure of carotenoids. (B) The process of absorption and metabolism of carotenoids. (C) The main intracellular targets of carotenoids.
  • antioxidant function, e.g., quenching (deactivating) singlet oxygen [11];
  • activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway and thus upregulation of the expression of antioxidant and detoxifying enzymes [12];
  • inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), in order to prevent its migration into the nucleus, causing a decrease in the production of inflammatory cytokines [12];
  • absorption of blue light by lutein, zeaxanthin, and meso-zeaxanthin in the retina of the eye.

4. Carotenoids and Hormones

4.1. Introduction

To this date, carotenoids and their derivatives were found to modulate many different endocrine axes, including influences on thyroid hormones, insulin, glucocorticoids, progesterone, estrogens as well as androgens, which is most interesting regarding PC. However, present studies offer inconsistent data on the nature of this interaction and thus it is often difficult to infer a definitive effect of the influence of carotenoids on distinct endocrine regulatory elements.
As mentioned, the crosstalk between carotenoids and androgens was examined. This interaction was possibly conserved during evolution, as in male birds, the carotenoid–testosterone interplay is pivotal for proper integumental coloration development [13]. However, experimental data are highly inconsistent, as carotenoids and their derivatives were shown to either increase [14,15], decrease [16,17,18], or have no effect on serum testosterone [19,20]. A possible explanation for this inconsistency is offered by other studies, showing that the genetic status of BCO1—the enzyme implicated in carotenoid central cleavage—may affect their interaction with testosterone levels in mice [21,22].
Additionally, LC is present at nanomolar concentrations in human semen, often bound to prostasomes. Prostasomes are multilayered vesicles secreted by acinar cells, composed mainly of fatty acids, cholesterol, and sphingomyelin. There is a constant exchange of substances between them and the sperm, which makes prostasomes important in the regulation of the sperm environment [23]. Possibly, LC in prostasomes acts as a free radical scavenger. However, more recent studies which would cover this subject are lacking.
Some carotenoids were also linked to the improvement of insulin-resistance and low-density lipoprotein (LDL) decrease [24,25,26]. Of note, high-density lipoproteins (HDLs) and LDLs are implicated in carotenoid transport in serum and cellular uptake and their relative abundance may affect the biological action of those compounds [27,28].

4.2. Carotenoid Metabolism

A recognized classical mechanism of the biological activity of carotenoids involves nuclear receptor (NR) signaling. However, to act as agonists of retinoid X receptors (RXRs) or retinoic acid receptors (RARs), carotenoids must undergo a series of reactions, catalyzed by different enzymes, to be converted into high-affinity ligands, in this case mostly into ATRA. Other metabolites, such as ω3-polyunsaturated fatty acids (ω3-PUFAs) are also potent for receptor binding, although with a lower affinity, whereas some do not necessarily induce its activation upon binding. For example retinal at high concentrations and asymmetric BC cleavage products, which may in fact inhibit NR signaling [29].
Following cellular uptake, retinol is converted into retinal by alcohol dehydrogenase (ADH) and short-chain dehydrogenase (SDR), and then into active ATRA by aldehyde dehydrogenase (ALDH). Apart from that, cytochrome B1 (CYPB1) is capable of converting retinol into retinal or directly into ATRA [29]. BC may enter this pathway after undergoing central oxidative cleavage by cytosolic BCO1 to form the retinal. Another enzyme, BCO2, residing within the mitochondria, is implicated in oxidative but eccentric cleavage of BC, generating other biologically active compounds [29]. Importantly, these products were shown to inhibit RXRα, RARs, peroxisome proliferator-activated receptor α (PPARα), PPARγ and PPARδ activation, as well as inducing growth inhibition in MCF-7 and Hs578T breast cancer cell lines [30,31,32,33,34].
BCO2 is suggested to play a physiological role in the degradation of excess carotenoids to prevent oxidative stress [30]. BCO1 differs in carotenoid affinity, thus partly explaining their different biological activity [33]. Moreover, in humans, BCO1 polymorphism was suggested to affect the biological effects of carotenoids [35]. Furthermore, in BCO1-knock-out mice, a compensatory upregulation of BCO2 was noticed, which was shown to affect LC treatment, as LC caused a significant serum and testicular testosterone level decrease [21]. Apart from that, ALDH distribution was also linked to the regulation of retinoid signaling in embryonic development, as a complex pattern of different ALDH form expression is found in embryos and the perturbation in this system may be lethal [29].
Carotenoids may also impact cell biology directly without being metabolized. These effects include gap junction regulation [36] and oxidative/antioxidant balance influence. In the case of the latter, carotenoids were shown to possess both antioxidant and pro-oxidant properties. The balance between these two actions is affected by carotenoid concentration, where treatment with high doses of carotenoids induced prooxidant effects as opposed to antioxidant properties of low dosage in vitro, as demonstrated for BC and LC in cultures of HT29 colon cancer and murine macrophage-like cell lines [36]. In addition, direct oxidative degradation of BC in the course of antioxidant action may give rise to carotenoid cleavage products (CCPs) that in turn increase oxidative stress by impairing mitochondrial function [30,37,38,39]. Another study provided evidence that oxygen availability may affect carotenoid action, as in cell-based systems, LC resulted in total protection from exposure to high energy radiation at 0% compared to no such effect with a 100% oxygen atmosphere [40]. Interestingly, manganese superoxide dismutase (Mn-SOD) polymorphism was linked to differences in cancer risk reduction due to higher serum carotenoid concentration, as observed in a human observational study [41], also pointing out to differential effects of carotenoids being related to the presence of reactive oxygen species. Distinct carotenoids may also differ in antioxidant properties due to varying relative lipid/water partition coefficients and, therefore, differences in intracellular distribution [36]. BC, residing in lipid membranes, was suggested to influence their properties, which may also be important for cellular fate [39].

4.3. Carotenoids, Nuclear Receptors and Transcription Factors

NRs are thought to be the largest group of transcription factors (TFs), capable of changing the expression of multiple target genes, thus playing a vital part in cellular homeostasis regulation. Although most NRs are ligand-activated, in some cases for the so-called “nuclear orphan receptors” (NORs) the ligand is yet to be identified or the receptor activity is regulated at a different level, for instance via post-translational modifications (PTMs) [42,43]. All of the below discussed NRs, except for retinoid orphan receptor α (RORα), β and γ (referred to also as NR1F1, NR1F2, NR1F3) undergo homo- or hetero-dimerization to facilitate their action as TFs [42]. From the point of view of carotenoid-mediated signaling, the most important NRs are RXRs and RARs, with the ligand being VA and its derivatives. In addition, one of the NORs—RORβ (NR1F2), sharing a similarity with RARs—was demonstrated to present a strong affinity for ATRA. At last, PPARδ, an NR implicated in the regulation of fatty acid oxidation and adipocyte differentiation, was also shown to be potent for retinoid-binding [42].
RXRs and RARs are two families of NRs, each consisting of three proteins encoded by different genes: RARα, β, γ (NR1B1, NR1B2, NR1B3) and RXRα, β, γ (NR2B1, NR2B2, NR2B3), respectively. Unlike some steroid receptors, both RXRs and RARs are believed to be localized mainly in the nucleus, independently of ligand presence—although they undergo constant nucleo-cytoplasmic shuttling, reaching a balance established by the availability of both ligand and dimerizing partners [42]. To actively regulate transcription of genes, both RXRs and RARs need to undergo dimerization with other NR, enabling them to bind specified regions in the promoter or enhancer regions of target genes, termed Retinoid X Receptor Responsive Elements (RXREs) and Retinoic Acid Receptor Responsive Elements (RAREs), respectively. Whereas RARs may act only as heterodimers with RXRs, the second may undergo homodimerization or heterodimerize with a member of many other NR families, such as RAR, liver X receptor (LXR), constitutive androgen receptor (CAR), farnesoid X receptor (FXR), PPAR, hepatocyte nuclear factor 4 (HNF4), Nr2f, vitamin D receptor (VDR), nuclear receptor-related 1 protein (Nurr1), pregnane X receptor (PXR) and triiodothyronine receptor (TR3) [42,44].
The majority of RAREs do not seem to be directly involved in gene expression regulation via the classical mechanism, suggesting other possible roles for RXRs and RARs in gene expression regulation, for instance by affecting deoxyribonucleic acid (DNA) structural changes (loop forming etc.) or contribution to the formation of other protein complexes [42]. Furthermore, complexity is reached as different heterodimers of RXR are thought to be differently dependent on ligand binding. This led to the classification of heterodimers into three classes: nonpermissive, permissive, and conditionally permissive (Table 2). There is increasing evidence that the type of reaction may also depend on the cell type and availability of cofactors [42,44]. Signaling termination may be mediated by ligand-bound receptor phosphorylation and subsequent ubiquitination, followed by proteasomal degradation.
Table 2. Nuclear receptors involved in the metabolism of carotenoid metabolites [44].
Given the role of androgen signaling in PC, it is important to understand its complex crosstalk with retinoid receptors. RXRα physically interacts with unliganded androgen receptor (AR) to act as a weak co-activator. However, RXRα diminishes dihydrotestosterone -mediated gene expression. On the other hand, independently of androgen presence, AR is thought to repress RXR transcriptional activity [45]. Moreover, RXR interaction with orphan NR CAR was also described to diminish the activity of the latter [44]. Furthermore, putative androgen-responsive element (ARE) was found in the RARα gene promoter, suggesting androgens may directly regulate its expression [46]. Of note, one study found that, upon prostate tumorigenesis, upregulation of RAR with subsequent downregulation of AR took place. This perturbation of a balance between AR and RAR coexisted with the inability of ATRA to induce cell proliferation in cancer cells, as it did in normal ones [47]. Conversely, stable expression of full-length AR in an AR-null PC-3 cell line was even shown to sensitize cells for retinoid inhibitory action [48].
However, it is also important to emphasize that many biological effects of carotenoids are thought to be independent of NR activation [42]. Research has highlighted the role of another TF, although not belonging to the NR superfamily, in mediating the biological action of carotenoids. The nuclear factor erythroid 2-related factor 2 encoded by Nuclear Factor, Erythroid 2 Like 2 (NFE2L2) gene is a basic leucine zipper (bZIP) protein, regarded as a master regulator of cellular antioxidative response [49]. Upon nuclear translocation, it binds to the antioxidant responsive element (AnRE) or electrophile-response element (EpRE) in the DNA to regulate the transcription of multiple target genes, such as NAD(P)H quinone oxidoreductase, glutamate-cysteine ligase, thioredoxin reductase 1, heme oxygenase-1 (HMOX-1), glutathione S-transferase, UDP-glucuronosyltransferase and multidrug resistance-associated proteins implicated predominantly in antioxidative response and xenobiotic metabolism [49]. Its physiological role, however, encompasses actions far beyond reducing oxidative and xenobiotic stress, including reducing inflammatory response, regulating autophagy, mitochondrial function, and cellular metabolism [49]. Mechanistically, for transcriptional activity, Nrf2 needs to dimerize with one of the small musculoaponeurotic fibrosarcoma (sMaf) proteins, bind to AnRE and recruit co-activators and nucleosome-remodeling complexes to facilitate RNA polymerase II-dependent transcription [49]. As Nrf2 messenger ribonucleic acid (mRNA) is constitutively expressed, most of its regulation occurs at the protein level. When synthetized in the cytosol, Nrf2 is abruptly sequestered by the kelch-like ECH-associated protein 1 (Keap1) homodimer, ultimately facilitating proteasomal degradation of Nrf2. Electrophilic or oxidative stress causes covalent modification of cysteine residues in Keap1, abrogating Keap1-Cul3-Nrf2 interaction, thus stabilizing the latter, facilitating its accumulation and nuclear translocation [49]. Interestingly, the results of in vitro studies suggest that Nrf2 regulation may also occur at the epigenetic level, via close regulation by micro RNAs (miRNAs) or DNA methylation [50]. Nrf2 was also shown to interact with the ATRA-RARα complex, which results in comprised AnRE binding and transcriptional activity of the first [50]. Unliganded RARα was also shown to bind Nrf2 at a different site, resulting in Nrf2 inhibition [50].
Therefore, Nrf2 in cancer biology may act as a tumor suppressor during initiation and promotion of carcinogenesis and conversely as an oncogene at late stages. Consistently, this ambiguity is reflected in PC biology. Enhanced Nrf2 signaling due to hypermethylation of Keap1 promoter or mutation of Keap1 or Nrf2 gene were reported in PC [50]. Conversely, in Transgenic Adenocarcinoma Mouse Prostate (TRAMP) mice, PC cells were characterized by hypermethylation of the Nrf2 promoter, resulting in a decrease in its activity [50]. Interestingly, a recent paper reported reactive oxygen species (ROS)-independent Nrf2 activation as a result of PC, which depended on endoplasmic reticulum-stress mediated GRP78/BiP translocation to the cell surface [51]. Importantly, Nrf2 was shown to be responsive to carotenoid regulation. LC, BC, phytoene as well as astaxanthin (AST) mediated Nrf2 nuclear translocation and enhanced Nrf2 target gene transcription [52]. However, carotenoids are hydrophobic, raising the question of whether Nrf2 is rather activated by their derivatives. Indeed, it is suggested that an α,β-unsaturated carbonyl group is required for the reaction with Keap1 and subsequent Nrf2 release and activation [53]. This property is characteristic only for xanthophylls such as AST, whereas other carotenoids are incapable of Nrf2 induction [53]. Furthermore, oxidation products of BCO1- and BCO2-mediated carotenoid metabolism such as apocarotenals or diapocarotenedials, as well as some derivatives of enzymatic cleavage by the 9′, 10′-monooxygenases, are potential candidates for direct activation of Nrf2 [53]. This again highlights the importance of carotenoid metabolism in their final biological action, as discussed in Section 5.

6. Carotenoids and Prostatic Physiology and Pathology Other Than PC

6.1. Lycopene

6.1.1. Prostatic Hyperplasia (PH)/Benign Prostatic Hyperplasia

LC is present mainly in the all-trans form, but interestingly, there is a prevalence of its cis isomers in either benign or malignant prostate tissues. Whether this cis-lycopene is the more biologically active form is not known. A recent investigation was conducted to explore the inhibiting effects of cis/trans isomers of LC on the development of PH in mice. In total, 90 mice were randomly divided into nine groups (10 mice/group). The animals received different daily doses of both LC isomers as an emulsion administered by gastric gavage in soybean oil and subcutaneous injections of testosterone propionate used to induce BPH. Three groups of animals, used as a control, received either saline, finasteride and pure emulsion with soybean oil as vehicle control. After 30 days, blood samples were taken, the mice were sacrificed, and prostates were dissected for histopathologic examination. This revealed that both oral administration of all-trans and cis-isomers attenuated testosterone-induced PH. Cis-lycopene markedly reduced the levels of serum testosterone, DHT and prostate acid phosphatase (PAP). The decrease observed in the all-trans lycopene groups as compared to the cis-isomer group was smaller, but still significant [123].
LC may be combined with Serenoa repens (SeR) and selenium (Se). SeR extract consists of substances with antiandrogenic action, an anti-inflammatory effect and an antiproliferative proapoptotic effect, mediated through the inhibition of growth factors [124], whereas Se is an essential micronutrient present in certain antioxidant enzymes such as SOD. Treatment with the LC-Se-SeR combination was more efficient than applying only SeR in preventing BPH, and it inhibited rat prostate growth by 83%, suggesting that Se and LC at pharmacological doses potentiate SeR proapoptotic efficacy for BPH. The molecular effects of an LC-Se-SeR combination included downregulation of Bcl-2, upregulation of Bax and induction of CASP9 [123].
Another study focused on levels of inhibitor of apoptosis proteins (IAPs)—direct inhibitors of CASPs—after combined therapy with LC-Se-SeR and each compound alone. The levels of proteins, i.e., a cellular inhibitor of apoptosis protein 1 (cIAP-1), cIAP-2, nuclear inhibitor of apoptosis protein (NIAP) and BIRC5 (survivin) in rats with experimental testosterone-dependent BPH were measured. SeR, Se and LC, either alone or in combination, did not modify cIAP-1 and cIAP-2 expression, but significantly reduced NIAP and BIRC5 expression. The decrease of NIAP and BIRC5 was pronounced after LC treatment, but the most profound after application of the LC-Se-SeR combination [125]. Interestingly, NIAP is present only in either benign or malicious overgrowth of the prostate and not in normal prostate cells, suggesting that IAP might play a role in these conditions [126].

6.1.2. Lycopene Metabolism, Impact on Prostate Physiology and Relation with Serum Testosterone

LC may exert multiple molecular effects. To a various extent, it may prevent oxidative DNA damage, induce phase II enzymes, decrease levels of proinflammatory cytokines, inhibit androgen activation and signaling, inhibit IGF-I signal transduction, inhibit Wingless-related integration site (Wnt)/β-catenin signaling, increase gap-junctional communication and interfere with growth factor signaling pathways, leading to cell cycle arrest and apoptosis induction [127]. Changes in testosterone levels exert an influence on LC metabolism. Castration increases hepatic LC in rats, whereas higher testosterone leads to reduced LC accumulation [128]. Further literature data suggest that a high intake of tomato phytochemicals and higher serum LC may reduce serum testosterone [129].
In a recent study, BCO1 knockout or WT mice received either a 10% tomato powder, a lycopene-containing (248 nmol/g) diet, or a control diet for 4 days, after which serum and testicle testosterone were measured. BCO1-/- mice fed with tomato powder, as well as those fed with LC, had decreased levels of both serum and testicular testosterone. The testosterone levels in WT mice did not change. The mechanism by which BCO1 knockout affects LC concentration and reduces testosterone levels remains unclear. A probable explanation emerges from the fact that expression of BCO2 is higher in BCO1-/- mice. BCO2, known to be responsible for eccentric cleavage of acyclic carotenoids (including LC) to form apo-carotenals, may metabolize LC to products, which exert their therapeutic effect by decreasing testosterone levels [128]. The key role of BCO2 in the metabolism of acyclic non-provitamin A carotenoids, such as LC, should be taken into consideration, as tomato-fed mice with BCO2 knockout had increased serum and tissue concentrations of LC [130].

6.1.3. Anti-Inflammatory Properties and Signal Transduction

In an attempt to explore the impact of LC on PC or prostate hyperplasia, PrEC was treated either with LC at a physiologically relevant concentration (2.0 µM) or placebo for 48 h and then lysed and fractionated. The obtained proteins were trypsinized and derivatized [131]. The authors of this comprehensive study, adopting a multi-dimensional approach, examined various effects of LC. Exposure to LC impaired proliferation of PrEC by downregulating the Akt/mTOR pathway and by upregulating genes with growth inhibitory effects. Exposure also altered several signaling pathways, e.g., inhibiting androgen signaling, downregulating TNF-α signaling, and deactivating the MAPK pathway.

6.1.4. Cytoprotection, Redox Homeostasis, Apoptosis

LC’s impact on proteins associated with apoptosis is shown in Table 6. GSTs are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione [132]. Some findings suggest that LC can elevate levels of phase II enzymes that can prevent cytotoxicity due to xenobiotic electrophiles and carcinogens. In this study [131], both glutathione-S-transferase omega 1 (GSTO1) and GSTP1 were upregulated by 11% and 17%, respectively, in PrECs treated with LC. Surprisingly, contrary to the aforementioned results, treatment of PrEC cultures with LC for 48 h did not evoke any observable apoptosis.
Table 6. The influence of lycopene on the expression of proteins involved in the process of apoptosis [131].
Hydrophobic carotenoids such as LC do not possess any electrophilic group and are unlikely to directly activate the Nrf2 and the EpRE/AnRE system. Therefore, it is rather the carotenoid oxidation products, such as their BCO1/2 cleavage products and further metabolites, that are the active mediators of the EpRE/AnRE system [133]. Oxidized derivatives of carotenoids can be found both in tomatoes and in human serum and tissues. They can be formed either by spontaneous oxidation, or as a result of chemical or enzymatic catalyzed oxidation.

6.2. Other Carotenoids

It was established earlier that BCO1 disruption impacts diverse physiological endpoints independent of dietary carotenoid intake, including the expression of genes controlling androgen metabolism. Mice lacking BCO1 exhibited reduced serum testosterone, prostatic AR signaling, and prostatic cellular proliferation. Analysis of prostatic morphology revealed decreases in gland weight and tissue testosterone concentration. Expression of the Ki-67 proliferation marker in BCO1-/- prostate tissue was distinctly reduced, corresponding to the aforementioned morphological changes. Expression analysis of 200 PC and androgen-related genes suggested that BCO1 loss significantly disrupted prostatic AR signaling, cell cycle progression, and proliferation [22].
Some authors decided to study other carotenoids. For instance, Chao Du et al. focused on the antioxidant effects of torulene and torularhodin. According to their findings, these compounds protect human prostate stromal cells from H2O2-induced oxidative stress damage via regulating Bcl-2/Bax mediated apoptosis. Moreover, pretreatment with torulene and torularhodin distinctly impaired H2O2-induced apoptosis in human prostate stromal cells (WPMY-1) through the scavenging of intracellular ROS and inhibition of malondialdehyde overproduction, as well as the activation of catalase (CAT), SOD and glutathione peroxidase (GPx) [134].
AST is another compound that was employed to reduce oxidative stress. In a study involving prostate epithelial cells (RWPE-1) and PC cells (PC-3), Chinese researchers tried to determine AST’s effects on oxidative stress induced by Cu2+ ions [135]. Cu2+ triggered apoptosis and accumulation of intracellular ROS and malondialdehyde in both cell lines. The addition of AST solutions could decrease MDA levels, increased mitochondrial membrane potential, and kept ROS stable in RWPE-1 cells. AST decreased SOD, Gpx and CAT activity in a PC-3 cell line treated with Cu2+. Interestingly, an opposite effect was observed in RWPE-1 cells, suggesting that AST’s protective properties in prostate epithelial cells go hand in hand with its disturbance of the antioxidant enzyme system in PC cells.
Retinoid derivatives of provitamin A carotenoids exert multiple molecular effects and play an important, but a somewhat vague role in the development and the physiology of the prostate gland. It was shown that androgens determine the development of urogenital sinus (UGS) into the prostate and bulbourethral gland in male mammals [136]. However, other molecular pathways involved in the initiation of prostate development are still poorly understood. According to a recent study, sex-specific ATRA signaling is required for the initiation of UGS bud development in mice. ALDH catalyzes the final step in ATRA synthesis. Enzymes from this group have restricted areas of expression in the urogenital mesenchyme (UGM), which surrounds the epithelium within the UGS of male embryos at the early stages of prostate development. As confirmed by reverse transcription-polymerase chain reaction (RT-PCR), Aldh1a1 and Aldh1a3 expression were sex-specific. They were undetected in the female UGS, while Aldh1a2 was present in both males and females. Moreover, Aldh1a1 and Aldh1a3 showed a rather peri-urethral expression pattern at the epithelial–mesenchymal boundary within the male UGM. Such a correlation suggested that ATRA might play a role in prostate development initiation. In an ex vivo organ culture assay with UGS from female mice embryos, the addition of DHT proved a prerequisite to induce prostate bud formation and expression of Nkx3.1 and Sox9, early markers of prostate development. However, female UGS cultured with DHT and DEAB (4-diethylamino-benzaldehyde), an inhibitor of ALDH enzymes, had a distinctly reduced number of buds along with a severe decrease in prostate development marker expression. The addition of ATRA to UGS cultures with DHT and DEAB reversed the aforementioned effect and reactivated the development of buds. The role of ATRA receptors was challenged using a pan RAR inverse agonist, BMS493. As expected, this impaired the formation of prostate buds [137].
Another example of androgen and ATRA cooperation emerged from a study focusing on human prostatic transglutaminase (hTGP) prostate-restricted gene regulation. TGP in rodents is related to fertilization and reduction of sperm antigenicity. In humans, hTGP expression corresponds to the invasive potential of PC cells. To investigate the impact of ATRA, the prostate cell lines LNCaP, PC346C, PNT1A and PNT2C2 were treated with 500 nM ATRA. LNCaP and PC346C cancer cells treated with ATRA showed a marked increase in hTGP expression, whereas the non-tumorigenic prostate cell lines PNT1A and PNT2C2 showed a small decrease. RARγ knockdown with siRNA targeting specifically RARγ m-RNA had a significant negative effect on basal hTGP mRNA expression and its levels in ATRA-treated cells. Consequently, it is probably RARγ that plays the major role in ATRA-dependent hTGP expression. The presence of AR, but not its activity, facilitated hTGP expression. Knockout of AR in LNCaP cells, both in untreated conditions and 24 h after ATRA treatment (500 nM), decreased hTGP expression. However, inhibition of ARs’ activation by bicalutamide had no effect on hTGP levels in LNCaP cells [138].
Lecithin: retinol acyltransferase (LRAT) is the major enzyme involved in retinol esterification in most tissues. Both LRAT and RA receptor 2 (RAR2) mRNA levels were higher in normal PrEC than in the PC-3 cell line. In accordance with a hypothesis that increasing LRAT expression can potentially reduce prostate tumor progression, combination therapies that increased the expression of both RARs and GATA TFs were set up. The study revealed that the 172-bp sequence from 14 to 186 in the human LRAT promoter contained essential regulatory elements required for LRAT transcription. PrEC and PC-3 were co-transfected with RARs and GATA-4, an RA-inducible GATA TF. The pLRAT186 human LRAT promoter–reporter construct was used to determine levels of LRAT. It was found that RA receptors and GATA TFs cooperated in response to ATRA and upregulated LRAT transcription in both PrEC and PC-3 cells [139].
Ethanol alters plasma retinol concentrations proportionally to its amount consumed, but it does not change the retinol concentration in the rat prostate. However, high consumption of ethanol increased the concentration of ATRA in plasma/prostate tissue and especially induced RARβ and RARγ in the dorsal prostate lobe. Ethanol consumption and increased ATRA levels did not affect cell proliferation and apoptosis in the prostate [140]. Both synthesis and catabolism of ATRA were modulated by ethanol consumption dose-dependent. CYP26A1 and CYP26B1 are responsible for ATRA catabolism. Ethanol reduced the activity of the aforementioned CYPs and increased ATRA concentration in the prostate. It also changed the levels of ALDHA1, ALDHA2 and ALDHA3, either elevating or decreasing their concentrations in different parts of the rat prostate [141].

7. Conclusions

This review presents insight into the recent findings on the influence of carotenoids and retinoids on prostate physiology and pathology, with special concern given to PC and PH. To find a link between the results in observational studies and the basic biology of PC, we reviewed many laboratory studies, including cell-culture and animal models. Many promising molecular targets for carotenoids were revealed, e.g., the IGF pathway and BCO polymorphisms for LC or HOXB13 for ATRA, indicating that the assessment of variants of genes coding for those proteins might be crucial for an effective PC therapy with carotenoids. Simultaneously, a small efficacy of BC was shown, supporting as well as explaining epidemiological findings.
The profound knowledge of the metabolism of various carotenoids and their derivatives would be associated with a deeper understanding of their effects on cellular receptors and signaling pathways, one of the keys to the development of a cutting-edge approach to the prophylaxis and treatment of prostate diseases, first and foremost PC—a severe threat to the health and life of millions of men in the world, which still poses a therapeutic challenge. The diversity of carotenoids and their influence on the human organism and prostate in particular still remains a source of fascinating, surprising findings. Undoubtedly, numerous discoveries in this field are awaiting us in the following years.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/antiox10040585/s1. PAGE ADRESS, Figure S1: The flow chart summarizing the process of data extraction.

Author Contributions

Conceptualization, J.D.-L., P.H. and T.B.; formal analysis, P.H., A.Ł., O.S., B.G., J.D.-L., Y.S., T.B., J.A.M., P.L.; writing, P.H., A.Ł., O.S., B.G., J.D.-L., Y.S., T.B., J.A.M.; review and editing, J.D.-L., T.B., P.H., A.Ł., O.S., B.G., Y.S., J.A.M., P.L.; visualization, P.H., J.D.-L.; drawings, P.H.; supervision, J.D.-L., T.B.; project administration, J.D.-L., T.B.; funding acquisition, J.D.-L., T.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the COST Action CA 15136 EUROCAROTEN.

Acknowledgments

The insights obtained by the COST Action CA 15136 EUROCAROTEN are much appreciated. This article is based upon work from the COST-EUROCAROTEN, supported by COST (European Cooperation in Science and Technology) and N41/DBS/000431.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

5-aza-dC—5-aza-2′-deoxycytidine, 15dPGJ2—15-deoxy-Δ12,14-prostaglandin J2, ABCA1—adenosine triphosphate-binding cassette transporter subfamily A member 1, ADH—alcohol dehydrogenase, AL—algal lycopene, ALDH—aldehyde dehydrogenase, AR—androgen receptor, ARE—androgen responsive element, ASAP—atypical small acinar proliferation, AST—astaxanthin, ATBC—Alpha-Tocopherol, Beta-Carotene Cancer Prevention (study), ATRA—all-trans-retinoic acid, AnRE—antioxidant responsive element, ApoAI—apolipoprotein AI, BC—β-carotene, BCO1 or 2—β-carotene 15, 15′-oxygenase 1 or 2, BIRC2—Baculoviral IAP repeat-containing protein 2, BPH—benign prostatic hyperplasia, Bax—Bcl-2-associated X protein, Bcl-2—B-cell lymphoma 2, CAPE—caffeic acid phenethyl ester, CAR—constitutive androgen receptor, CASP—caspase, CAT—catalase, CCP—carotenoid cleavage product, CD—cluster of differentiation, CI—combination index, CK18—cytokeratin 18, CMV—cytomegalovirus, COX-2—cyclooxygenase 2, CRABP-II—cellular retinoic acid binding protein-II, CRPC—castration-resistant prostate cancer, CYPB1—cytochrome B1, Cdk—cyclin-dependent kinase, DBD—deoxyribonucleic acid binding domain, DEAB—4-diethylamino-benzaldehyde, DHT—dihydrotestosterone, DNA—deoxyribonucleic acid, DNMT3b—DNA methyltransferase 3b, DRE—digital rectal examination, ECE1—endothelin converting enzyme 1, EGFR—epidermal growth factor receptor, ELOVL2—elongation of very long chain fatty acids protein 2, ER—estrogen receptor, EpRE—electrophile-response element, FABP5—fatty acid binding protein-5, FADD—Fas-associated protein with death domain, FGF—fibroblast growth factor, FXR—farnesoid X receptor, FasL—Fas ligand, GS—Gleason score, GSK-3β—glycogen synthase kinase 3β, GSTO1—glutathione-S-transferase omega 1, GSTP1—glutathione S-transferase P1, Gpx—glutathione peroxidase, HDAC—histone deacetylase, HDL—high-density lipoprotein, HGPIN—high grade prostatic intraepithelial neoplasia, HIF1α—hypoxia-inducible factor 1-α, HMG-CoAR—hydroxymethylglutaryl-CoA reductase, HMOX-1—heme oxygenase 1, HNF4—Hepatocyte nuclear factor 4, IC50—half-maximal inhibitory concentration, ICAM1—intercellular adherence molecule 1, IDO—Indoleamine-pyrrole 2,3-dioxygenase, IGF-1—insulin-like growth factor 1, IGF-BP3—insulin-like growth factor binding protein 3, IGF-IR—insulin-like growth factor-I receptor, IL—interleukin, IκB—inhibitor of kappa B, JNK—Jun N-terminal kinase, KLK—kallikrein, Keap1—kelch-like ECH-associated protein 1, LB—lycopene beadlets, LBD—ligand binding domain, LC—lycopene, LDL—low-density lipoprotein, LRAT—lecithin:retinol acyltransferase, LTβR—lymphotoxin beta receptor, LXR—liver X receptor, MCL-1—myeloid cell leukemia 1, MENS—The Molecular Effects of Nutritional Supplement, MHC—major histocompatibility complex, MMP9—matrix metalloprotease 9, MOOSE—Meta-analysis of Observational Studies in Epidemiology, MSK1—mitogen- and stress-activated protein kinase 1, MTTP—microsomal triglyceride transfer protein, NCoA—nuclear co-activator, NCoR—nuclear co-repressor, NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells, NFE2L2—Nuclear Factor Erythroid 2 Like 2, NIAP—nuclear inhibitor of apoptosis protein, NICE—National Institute for Health and Clinical Excellence, NLS—nuclear localization signal, NOR—nuclear orphan receptor, NOS—Newcastle-Ottawa Scale, NR—nuclear receptor, Nrf2—nuclear factor E2-related factor 2, Nurr1—Nuclear receptor related 1 protein, PAP—prostatic acid phosphatase, PC—prostate cancer, PF-4—platelet factor-4, PH—prostatic hyperplasia, PI3K—phosphatidylinositol 3-kinase, PPAR—peroxisome proliferator-activated receptor, PSA—prostate specific antigen, PTEN—phosphatase and tensin homolog, PTM—post-translational modification, PXR—pregnane X receptor, PoS—placebo sera, RAE—retinol activity equivalent, RARE—Retinoic Acid Receptor Responsive Element, RARα—retinoic acid receptor α, RASP—N1,N12-bis(all-trans-retinoyl)spermine, RBP—retinol binding protein, RCT—randomized controlled trial, ROR (or NR1F)—retinoid orphan receptor, ROS—reactive oxygen species, RT—red tomato paste, RT-PCR—reverse transcription polymerase chain reaction, RTS—red tomato sera, RXR—retinoid X receptor, RXRE—Retinoid X Receptor Responsive Element, Rho-GTP-ase—Ras homolog family member guanosine triphosphate hydrolase, SCARB1—scavenger receptor class B type 1, SCNC—small cell neuroendocrine carcinoma, SDR—short-chain dehydrogenase, SKI—TGF-β signaling repressor, SNP—single nucleotide polymorphism, SOCS2—suppressor of cytokine signaling 2, SOD—superoxide dismutase, STAT—signal transducer and activator of transcription, SeR—Serenoa repens, TAM—tumor-associated macrophage, TC—tomato LC, TF—transcription factor, TGF-β—transforming growth factor beta, TM—thrombomodulin, TNFRSF—tumor necrosis factor receptor superfamily, TNF-α—tumor necrosis factor α, TP—tomato powder, TP53—tumor protein 53, TR3—triiodothyronine receptor, TRAMP—Transgenic Adenocarcinoma Mouse Prostate, UGM—urogenital mesenchyme, UGS—urogenital sinus, VA—vitamin A, VCAM—vascular cell adhesion molecule, VD—vitamin D, VDR—vitamin D receptor, VEGF—vascular and epithelial growth factor, WT—wild-type, Wnt—Wingless-related integration site, YT—yellow tomato paste, YTS—yellow tomato sera, bZIP—basic leucine zipper, cDNA—complementary DNA, cIAP-1—cellular inhibitor of apoptosis protein 1, hTGP—human prostatic transglutaminase, mRNA—messenger ribonucleic acid, mTOR—mechanistic target of rapamycin, miRNA—micro RNA, p38-MAPK—p38-mitogen-activated protein kinase, sMaf—small musculoaponeurotic fibrosarcoma, siRNA—small inhibitory RNA, tRXR—truncated RXR, ω3-PUFA—ω3-polyunsaturated fatty acid.

References

  1. Wang, Y.; Cui, R.; Xiao, Y.; Fang, J.; Xu, Q. Effect of Carotene and Lycopene on the Risk of Prostate Cancer: A Systematic Review and Dose-Response Meta-Analysis of Observational Studies. PLoS ONE 2015, 10, e0137427. [Google Scholar]
  2. Abar, L.; Vieira, A.R.; Aune, D.; Stevens, C.; Vingeliene, S.; Navarro Rosenblatt, D.A.; Chan, D.; Greenwood, D.C.; Norat, T. Blood concentrations of carotenoids and retinol. Cancer Med. 2016, 5, 2069–2083. [Google Scholar] [CrossRef] [PubMed]
  3. Beydoun, M.A.; Chen, X.; Jha, K.; Beydoun, H.; Zonderman, A.; Canas, J. Carotenoids, vitamin A, and their association with the metabolic syndrome: A systematic review and meta-analysis. Nutr. Rev. 2018, 77, 32–45. [Google Scholar] [CrossRef]
  4. Zu, K.; Mucci, L.; Rosner, B.A.; Clinton, S.K.; Loda, M.; Stampfer, M.J.; Giovannucci, E. Dietary lycopene, angiogenesis, and prostate cancer: A prospective study in the prostate-specific antigen era. J. Natl. Cancer Inst. 2014, 106, djt430. [Google Scholar] [CrossRef]
  5. Ross, C.; Caballero, B.H.; Cousins, R.J.; Tucker, K.L.; Ziegler, T.R. Modern Nutrition in Health and Disease, 11th ed.; Wolters Kluwer Health Adis (ESP): Philadelphia, PA, USA, 2012. [Google Scholar]
  6. Armstrong, G.A.; Hearst, J.E. Carotenoids 2: Genetics and molecular biology of carotenoid pigment biosynthesis. FASEB J. 1996, 10, 228–237. [Google Scholar] [CrossRef] [PubMed]
  7. Kiokias, S.; Proestos, C.; Varzakas, T.H. A Review of the Structure, Biosynthesis, Absorption of Carotenoids-Analysis and Properties of their Common Natural Extracts. Curr. Res. Nutr. Food Sci. 2015, 4, 25–37. [Google Scholar] [CrossRef]
  8. Fiedor, J.; Burda, K. Potential Role of Carotenoids as Antioxidants in Human Health and Disease. Nutrients 2014, 6, 466–488. [Google Scholar] [CrossRef] [PubMed]
  9. Cvetkovic, D.; Nikolic, G. Carotenoids, 1st ed.; IntechOpen: London, UK, 2017. [Google Scholar]
  10. Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids; The National Academies Press (US): Washington, DC, USA, 2000.
  11. Young, A.J.; Lowe, G. Antioxidant and Prooxidant Properties of Carotenoids. Arch. Biochem. Biophys. 2001, 385, 20–27. [Google Scholar] [CrossRef] [PubMed]
  12. Kaulmann, A.; Bohn, T. Carotenoids, inflammation, and oxidative stress—implications of cellular signaling pathways and relation to chronic disease prevention. Nutr. Res. 2014, 34, 907–929. [Google Scholar] [CrossRef]
  13. Blas, J.; Pérez-Rodríguez, L.; Bortolotti, G.R.; Viñuela, J.; Marchant, T.A. Testosterone increases bioavailability of carotenoids: Insights into the honesty of sexual signaling. Proc. Natl. Acad. Sci. USA 2006, 103, 18633–18637. [Google Scholar] [CrossRef]
  14. Munetsuna, E.; Hojo, Y.; Hattori, M.; Ishii, H.; Kawato, S.; Ishida, A.; Kominami, S.A.J.; Yamazaki, T. Retinoic Acid Stimulates 17β-Estradiol and Testosterone Synthesis in Rat Hippocampal Slice Cultures. Endocrinology 2009, 150, 4260–4269. [Google Scholar] [CrossRef]
  15. Haider, S.G. Cell Biology of Leydig Cells in the Testis. Int. Rev. Cytol. 2004, 233, 181–241. [Google Scholar] [PubMed]
  16. Gaál, A.; Csaba, G. Testosterone and progesterone level alterations in the adult rat after retinoid (retinol or retinoic acid) treatment (imprinting) in neonatal or adolescent age. Horm. Metab. Res. 1998, 30, 487–489. [Google Scholar] [CrossRef] [PubMed]
  17. Campbell, J.K.; Stroud, C.K.; Nakamura, M.T.; Lila, M.A.; Erdman, J.W., Jr. Serum Testosterone Is Reduced Following Short-Term Phytofluene, Lycopene, or Tomato Powder Consumption in F344 Rats. J. Nutr. 2006, 136, 2813–2819. [Google Scholar] [CrossRef] [PubMed]
  18. Wan, L.; Tan, H.-L.; Thomas-Ahner, J.M.; Pearl, D.K.; Erdman, J.W., Jr.; Moran, N.E.; Clinton, S.K. Dietary Tomato and Lycopene Impact Androgen Signaling- and Carcinogenesis-Related Gene Expression during Early TRAMP Prostate Carcinogenesis. Cancer Prev. Res. 2014, 7, 1228–1239. [Google Scholar] [CrossRef]
  19. Angioni, A.R.; Lania, A.; Cattaneo, A.; Beck-Peccoz, P.; Spada, A. Effects of chronic retinoid administration on pituitary function. J. Endocrinol. Investig. 2005, 28, 961–964. [Google Scholar] [CrossRef] [PubMed]
  20. Hughes, G.S., Jr.; Ringer, T.V.; Francom, S.F.; Means, L.K.; DeLoof, M.J. Lack of effects of beta-carotene on lipids and sex steroid hormones in hyperlipidemics. Am. J. Med. Sci. 1994, 145, 16–22. [Google Scholar] [CrossRef]
  21. Kawata, A.; Murakami, Y.; Suzuki, S.; Fujisawa, S. Anti-inflammatory Activity of β-Carotene, Lycopene and Tri-n-butylborane, a Scavenger of Reactive Oxygen Species. In Vivo 2018, 32, 255–264. [Google Scholar]
  22. Smith, J.W.; Ford, N.A.; Thomas-Ahner, J.M.; Moran, N.E.; Bolton, E.C.; Wallig, M.A.; Clinton, S.K.; Erdman Jr, J.W. Mice lacking β-carotene-15,15’-dioxygenase exhibit reduced serum testosterone, prostatic androgen receptor signaling, and prostatic cellular proliferation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2016, 311, R1135–R1148. [Google Scholar] [CrossRef]
  23. Goyal, A.; Delves, G.H.; Chopra, M.; Lwaleed, B.A.; Cooper, A.J. Can lycopene be delivered into semen via prostasomes? In vitro incorporation and retention studies. Int. J. Androl. 2006, 29, 528–533. [Google Scholar] [CrossRef]
  24. Blondin, S.A.; Yeung, E.H.; Mumford, S.L.; Zhang, C.; Browne, R.W.; Wactawski-Wende, J.; Schisterman, E.F. Serum Retinol and Carotenoids in Association with Biomarkers of Insulin Resistance among Premenopausal Women. ISRN Nutr. 2013, 2013, 619516. [Google Scholar] [CrossRef]
  25. Sugiura, M.; Nakamura, M.; Ogawa, K.; Ikoma, Y.; Yano, M. High-serum carotenoids associated with lower risk for developing type 2 diabetes among Japanese subjects: Mikkabi cohort study. BMJ Open Diabetes Res. Care 2015, 3, e000147. [Google Scholar] [CrossRef]
  26. Ried, K.; Fakler, P. Protective effect of lycopene on serum cholesterol and blood pressure: Meta-analyses of intervention trials. Maturitas 2011, 68, 299–310. [Google Scholar] [CrossRef]
  27. Traber, M.G.; Diamond, S.R.; Lane, J.C.; Brody, R.I.; Kayden, H.J. beta-Carotene transport in human lipoproteins. Comparisons with a-tocopherol. Lipids 1994, 29, 665–669. [Google Scholar] [CrossRef] [PubMed]
  28. Harrison, E.H. Mechanisms of Transport and Delivery of Vitamin A and Carotenoids to the Retinal Pigment Epithelium. Mol. Nutr. Food Res. 2019, 63, 1801046. [Google Scholar] [CrossRef] [PubMed]
  29. Noy, N. Retinoid-binding proteins: Mediators of retinoid action. Biochem. J. 2000, 3, 481–495. [Google Scholar] [CrossRef]
  30. Harrison, E.H.; dela Sena, C.; Eroglu, A.; Fleshman, M.K. The formation, occurrence, and function of β-apocarotenoids: β-carotene metabolites that may modulate nuclear receptor signaling. Am. J. Clin. Nutr. 2012, 5, 1189S–1192S. [Google Scholar] [CrossRef]
  31. Rao, A.V.; Rao, L.G. Carotenoids and human health. Pharmacol. Res. 2007, 55, 207–216. [Google Scholar] [CrossRef]
  32. van Helden, Y.G.J.; Godschalk, R.W.L.; Swarts, H.J.M.; Hollman, P.C.H.; van Schooten, F.J.; Keijer, J. Beta-carotene affects gene expression in lungs of male and female Bcmo1 −/− mice in opposite directions. Cell. Mol. Life Sci. 2011, 68, 489–504. [Google Scholar] [CrossRef][Green Version]
  33. Ford, N.A.; Moran, N.E.; Smith, J.W.; Clinton, S.K.; Erdman, J.W., Jr. An interaction between carotene-15,15′-monooxygenase expression and consumption of a tomato or lycopene-containing diet impacts serum and testicular testosterone. Int. J. Cancer 2012, 131, E133–E148. [Google Scholar] [CrossRef]
  34. Tibaduiza, E.C.; Fleet, J.C.; Russell, R.M.; Krinsky, N.I. Excentric Cleavage Products of β-Carotene Inhibit Estrogen Receptor Positive and Negative Breast Tumor Cell Growth In Vitro and Inhibit Activator Protein-1-Mediated Transcriptional Activation. J. Nutr. 2002, 132, 1368–1375. [Google Scholar] [CrossRef] [PubMed]
  35. Milani, A.; Basirnejad, M.; Shahbazi, S.; Bolhassani, A. Carotenoids: Biochemistry, pharmacology and treatment. Br. J. Pharmacol. 2017, 174, 1290–1324. [Google Scholar] [CrossRef] [PubMed]
  36. Lowe, G.M.; Booth, L.A.; Young, A.J.; Bilton, R.F. Lycopene and beta-carotene protect against oxidative damage in HT29 cells at low concentrations but rapidly lose this capacity at higher doses. Free Radic. Res. 1999, 30, 141–151. [Google Scholar] [CrossRef]
  37. Siems, W.; Sommerburg, O.; Schild, L.; Augustin, W.; Langhans, C.-D.; Wiswedel, I. Beta-carotene cleavage products induce oxidative stress in vitro by impairing mitochondrial respiration. FASEB J. 2002, 16, 1289–1291. [Google Scholar] [CrossRef]
  38. Siems, W.; Wiswedel, I.; Salerno, C.; Crifò, C.; Augustin, W.; Schild, L.; Langhans, C.-D.; Sommerburg, O. Beta-carotene breakdown products may impair mitochondrial functions--potential side effects of high-dose beta-carotene supplementation. J. Nutr. Biochem. 2005, 16, 385–397. [Google Scholar] [CrossRef] [PubMed]
  39. Young, A.J.; Lowe, G.L. Carotenoids-Antioxidant Properties. Antioxidants 2018, 7, 28. [Google Scholar] [CrossRef]
  40. Petersen, R.C. Free-radicals and advanced chemistries involved in cell membrane organization influence oxygen diffusion and pathology treatment. AIMS Biophys. 2017, 4, 240–283. [Google Scholar] [CrossRef]
  41. Li, H.; Kantoff, P.W.; Giovannucci, E.; Leitzmann, M.F.; Gaziano, J.M.; Stampfer, M.J.; Ma, J. Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. Cancer Res. 2005, 65, 2498–2504. [Google Scholar] [CrossRef]
  42. Robinson-Rechavi, M.; Garcia, H.E.; Laudet, V. The nuclear receptor superfamily. J. Cell Sci. 2003, 116, 585–586. [Google Scholar] [CrossRef]
  43. Mandal, S.S. Gene Regulation, Epigenetics and Hormone Signaling, 1st ed.; Wiley-VCH Verlag GmbH & Co. KGaA: New York, NY, USA, 2017. [Google Scholar]
  44. Dawson, M.I.; Xia, Z. The Retinoid X Receptors and Their Ligands. Biochim. Biophys. Acta 2012, 1821, 21–56. [Google Scholar] [CrossRef]
  45. Chuang, K.-H.; Lee, Y.-F.; Lin, W.-J.; Chu, C.-Y.; Altuwaijri, S.; Wan, Y.-J.Y.; Chang, C. 9-cis-Retinoic Acid Inhibits Androgen Receptor Activity through Activation of Retinoid X Receptor. Mol. Endocrinol. 2005, 19, 1200–1212. [Google Scholar] [CrossRef][Green Version]
  46. Li, M.-T.; Richter, F.; Chang, C.; Irwin, R.J.; Huang, H. Androgen and retinoic acid interaction in LNCaP cells, effects on cell proliferation and expression of retinoic acid receptors and epidermal growth factor receptor. BMC Cancer 2002, 10, 16. [Google Scholar] [CrossRef] [PubMed][Green Version]
  47. Richter, F.; Huang, H.F.S.; Li, M.-T.; Danielpour, D.; Wang, S.-L.; Irwin, R.J., Jr. Retinoid and androgen regulation of cell growth, epidermal growth factor and retinoic acid receptors in normal and carcinoma rat prostate cells. Mol. Cell. Endocrinol. 1999, 153, 29–38. [Google Scholar] [CrossRef]
  48. Murthy, S.; Marcelli, M.; Weigel, N.L. Stable expression of full length human androgen receptor in PC-3 prostate cancer cells enhances sensitivity to retinoic acid but not to 1?,25-dihydroxyvitamin D3. Prostate 2003, 56, 293–304. [Google Scholar] [CrossRef] [PubMed]
  49. Vomund, S.; Schäfer, A.; Parnham, M.J.; Brüne, B.; von Knethen, A. Nrf2, the Master Regulator of Anti-Oxidative Responses. Int. J. Mol. Sci. 2017, 18, 2772. [Google Scholar] [CrossRef]
  50. Jung, B.-J.; Yoo, H.-S.; Shin, S.; Park, Y.-J.; Jeon, S.-M. Dysregulation of NRF2 in Cancer: From Molecular Mechanisms to Therapeutic Opportunities. Biomol. Ther. 2018, 26, 57–68. [Google Scholar] [CrossRef]
  51. Ilaria, B.; Scarpelli, P.; Pizzo, S.V.; Grottelli, S. ROS-independent Nrf2 activation in prostate cancer. Oncotarget 2017, 8, 67506–67518. [Google Scholar]
  52. Ben-Dor, A.; Steiner, M.; Gheber, L.; Danilenko, M.; Dubi, N.; Linnewiel, K.; Zick, A.; Sharoni, Y.; Levy, J. Carotenoids activate the antioxidant response element transcription system. Mol. Cancer Ther. 2005, 4, 177–186. [Google Scholar]
  53. Barros, M.; Rodrigo, M.J.; Zacarías, L. Dietary Carotenoid Roles in Redox Homeostasis and Human Health. J. Agric. Food Chem. 2018, 66, 5733–5740. [Google Scholar] [CrossRef]
  54. Boon, S.; McClements, J.; Weiss, J.; Decker, E. Factors influencing the chemical stability of carotenoids in foods. Crit. Rev. Food. Sci. Nutr. 2010, 50, 515–532. [Google Scholar] [CrossRef] [PubMed]
  55. Böhm, V.; Lietz, G.; Olmedilla-Alonso, B.; Phelan, D.; Reboul, E.; Bánati, D.; Borel, P.; Corte-Real, J.; de Lera, A.R.; Desmarchelier, C.; et al. From carotenoid intake to carotenoid blood and tissue concentrations-implications for dietary intake recommendations. Nutr. Rev. 2020, 1–30. [Google Scholar] [CrossRef]
  56. Morgenstern, J.; Fleming, T.; Kliemank, E.; Brune, M.; Nawroth, P.; Fischer, A. Quantification of All-Trans Retinoic Acid by Liquid Chromatography-Tandem Mass Spectrometry and Association with Lipid Profile in Patients with Type 2 Diabetes. Metabolites 2021, 11, 60. [Google Scholar] [CrossRef] [PubMed]
  57. Dulińska-Litewka, J.; Hałubiec, P.; Łazarczyk, A.; Szafrański, O.; Sharoni, Y.; McCubrey, J.A.; Gąsiorkiewicz, B.; Bohn, T. Recent Progress in Discovering the Role of Carotenoids and Metabolites in Prostatic Physiology and Pathology—A Review—Part II: Carotenoids in the Human Studies. Antioxidants 2021, 10, 319. [Google Scholar] [CrossRef] [PubMed]
  58. Gontero, P.; Marra, G.; Soria, F.; Oderda, M.; Zitella, A.; Baratta, F.; Chiorino, G.; Gregnanin, I.; Daniele, L.; Cattel, L.; et al. A Randomized Double-Blind Placebo Controlled Phase I–II Study on Clinical and Molecular Effects of Dietary Supplements in Men With Precancerous Prostatic Lesions. Chemoprevention or “Chemopromotion”? Prostate 2015, 75, 1177–1186. [Google Scholar] [CrossRef] [PubMed]
  59. Heinonen, O.P.; Huttunen, J.K.; Albanes, D.; Haapakoski, J.; Palmgren, J.; Pietinen, P.; Pikkarainen, J.; Rautalahti, M.; Virtamo, J.; Edwards, B.K.; et al. The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers. N. Engl. J. Med. 1994, 330, 1029–1035. [Google Scholar]
  60. Bohn, T.; Desmarchelier, C.; Dragsted, L.O.; Nielsen, C.S.; Stahl, W.; Rühl, R.; Keijer, J.; Borel, P. Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans. Mol. Nutr. Food Res. 2017, 61, 1600685. [Google Scholar] [CrossRef] [PubMed]
  61. Desmarchelier, C.; Borel, P. Overview of carotenoid bioavailability determinants: From dietary factors to host genetic variations. Trends Food Sci. Technol. 2017, 69, 270–280. [Google Scholar] [CrossRef]
  62. Gong, X.; Marisiddaiah, R.; Zaripheh, S.; Wiener, D.; Rubin, L.P. Mitochondrial β-Carotene 9′,10′ Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function. Mol. Cancer Res. 2016, 14, 966–975. [Google Scholar] [CrossRef] [PubMed]
  63. Tang, Y.; Parmakhtiar, B.; Simoneau, A.R.; Xie, J.; Fruehauf, J.; Lilly, M.; Zi, X. Lycopene enhances docetaxel’s effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia 2011, 13, 108–119. [Google Scholar] [CrossRef]
  64. Yang, C.-M.; Lu, Y.-L.; Chen, H.-Y.; Hu, M.-L. Lycopene and the LXRα agonist T0901317 synergistically inhibit the proliferation of androgen-independent prostate cancer cells via the PPARγ-LXRα-ABCA1 pathway. J. Nutr. Biochem. 2012, 23, 1155–1162. [Google Scholar] [CrossRef]
  65. Yang, C.-M.; Lu, I.-H.; Chen, H.-Y.; Hu, M.-L. Lycopene inhibits the proliferation of androgen-dependent human prostate tumor cells through activation of PPARγ-LXRα-ABCA1 pathway. J. Nutr. Biochem. 2012, 23, 8–17. [Google Scholar] [CrossRef] [PubMed]
  66. European Patent Office. Method of Preparing Lycopene-Enriched Formulations That Are Free of Organic Solvents, Formulations Thus Obtained, Compositions Comprising Said Formulations and Use of Same. Available online: https://patents.google.com/patent/EP1886719A1 (accessed on 2 February 2021).
  67. Rafi, M.M.; Kanakasabai, S.; Reyes, M.D.; Bright, J.J. Lycopene modulates growth and survival associated genes in prostate cancer. J. Nutr. Biochem. 2013, 24, 1724–1734. [Google Scholar] [CrossRef]
  68. da Costa Pereira Soares, N.; Teodoro, A.J.; Oliveira, F.L.; do Nascimento Santos, C.A.; Takiya, C.M.; Saback Junior, C.M.O.; Bianco, M.; Palumbo Junior, A.; Nasciutti, L.E.; Ferreira, L.B.; et al. Influence of lycopene on cell viability, cell cycle, and apoptosis of human prostate cancer and benign hyperplastic cells. Nutr. Cancer 2013, 65, 1076–1085. [Google Scholar] [CrossRef] [PubMed]
  69. Renju, G.L.; Kurup, G.M.; Bandugula, V.R. Effect of lycopene isolated from Chlorella marina on proliferation and apoptosis in human prostate cancer cell line PC-3. Tumor Biol. 2014, 35, 10747–10758. [Google Scholar] [CrossRef] [PubMed]
  70. da Costa Pereira Soares, N.; Machado, C.L.; Trindade, B.B.; do Canto Lima, I.C.; Gimba, E.R.P.; Teodoro, A.J.; Takiya, C.; Borojevic, R. Lycopene Extracts from Different Tomato-Based Food Products Induce Apoptosis in Cultured Human Primary Prostate Cancer Cells and Regulate TP53, Bax and Bcl-2 Transcript Expression. Asian Pac. J. Cancer Prev. 2017, 18, 339–345. [Google Scholar]
  71. Linnewiel-Hermoni, K.; Khanin, M.; Danilenko, M.; Zango, G.; Amosi, Y.; Levy, J.; Sharoni, Y. The anti-cancer effects of carotenoids and other phytonutrients resides. Arch. Biochem. Biophys. 2015, 572, 28–35. [Google Scholar] [CrossRef]
  72. Assar, E.A.; Vidalle, M.C.; Chopra, M.; Hafizi, S. Lycopene acts through inhibition of IκB kinase to suppress NF-κB signaling in human prostate and breast cancer cells. Tumor biol. 2016, 37, 9375–9385. [Google Scholar] [CrossRef]
  73. da Costa Pereira Soares, N.; de Barros Elias, M.; Machado, C.L.; Trindade, B.B.; Borojevic, R.; Teodoro, A.J. Comparative Analysis of Lycopene Content from Different Tomato-Based Food Products on the Cellular Activity of Prostate Cancer Cell Lines. Foods 2019, 8, 201. [Google Scholar] [CrossRef]
  74. Kolberg, M.; Pedersen, S.; Bastani, N.E.; Carlsen, H.; Blomhoff, R.; Paur, I. Tomato paste alters NF-κB and cancer-related mRNA expression in prostate cancer cells, xenografts, and xenograft microenvironment. Nutr. Cancer 2015, 67, 305–315. [Google Scholar] [CrossRef]
  75. Elgass, S.; Cooper, A.; Chopra, M. Lycopene treatment of prostate cancer cell lines inhibits adhesion and migration properties of the cells. Int. J. Med. Sci. 2014, 11, 948–954. [Google Scholar] [CrossRef][Green Version]
  76. Linnewiel-Hermoni, K.; Motro, Y.; Miller, Y.; Levy, J.; Sharoni, Y. Carotenoid derivatives inhibit nuclear factor kappa B activity in bone and cancer cells by targeting key thiol groups. Free Radic. Biol. Med. 2014, 75, 105–120. [Google Scholar] [CrossRef]
  77. Palozza, P.; Colangelo, M.; Simone, R.; Catalano, A.; Boninsegna, A.; Lanza, P.; Monego, G.; Ranelletti, F.O. Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras. Carcinogenesis 2010, 31, 1813–1821. [Google Scholar] [CrossRef]
  78. Li, D.; Chen, L.; Zhao, W.; Hao, J.; An, R. MicroRNA-let-7f-1 is induced by lycopene and inhibits cell proliferation and triggers apoptosis in prostate cancer. Mol. Med. Rep. 2016, 13, 2708–2714. [Google Scholar] [CrossRef]
  79. Du, C.; Li, Y.; Guo, Y.; Han, M.; Zhang, W.; Qian, H. The suppression of torulene and torularhodin treatment on the growth of PC-3 xenograft prostate tumors. Biochem. Biophys. Res. Commun. 2016, 496, 1146–1152. [Google Scholar] [CrossRef] [PubMed]
  80. Tjahjodjati; Sugandi, S.; Umbas, R.; Satari, M. The Protective Effect of Lycopene on Prostate Growth Inhibitory Efficacy by Decreasing Insulin Growth Factor-1 in Indonesian Human Prostate Cancer Cells. Res. Rep. Urol. 2020, 2020, 137–143. [Google Scholar]
  81. Liu, A.G.; Erdman, J.W., Jr. Lycopene and apo-10′-lycopenal do not alter DNA methylation of GSTP1 in LNCaP cells. Biochem. Biophys. Res. Commun. 2011, 412, 479–482. [Google Scholar] [CrossRef] [PubMed]
  82. Konijeti, R.; Henning, S.; Moro, A.; Sheikh, A.; Elashoff, D.; Shapiro, A.; Ku, M.; Said, J.W.; Heber, D.; Cohen, P.; et al. Chemoprevention of prostate cancer with lycopene in the TRAMP model. Prostate 2010, 70, 1547–1554. [Google Scholar] [CrossRef] [PubMed]
  83. Cervi, D.; Pak, B.; Venier, N.; Sugar, L.; Nam, R.K.; Fleshner, N.E.; Klotz, L.; Venkateswaran, V. Micronutrients attenuate progression of prostate cancer by elevating the endogenous inhibitor of angiogenesis, platelet factor-4. BMC Cancer 2010, 10, 258. [Google Scholar] [CrossRef] [PubMed]
  84. Karabulut, B.; Karaca, B.; Atmaca, H.; Kisim, A.; Uzunoglu, S.; Sezgin, C.; Uslu, R. Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and zoledronic acid in hormone-refractory prostate cancer cell lines. Mol. Biol. Rep. 2010, 38, 249–259. [Google Scholar] [CrossRef]
  85. Sadikoglou, E.; Magoulas, G.; Theodoropoulou, C.; Athanassopoulos, C.M.; Giannopoulou, E.; Theodorakopoulou, O.; Drainas, D.; Papaioannou, D.; Papadimitriou, E. Effect of conjugates of all-trans-retinoic acid and shorter polyene chain analogues with amino acids on prostatecancer cell growth. Eur. J. Med. Chem. 2009, 44, 3175–3187. [Google Scholar] [CrossRef]
  86. Vourtsis, D.; Lamprou, M.; Sadikoglou, E.; Giannou, A.; Theodorakopoulou, O.; Sarrou, E.; Magoulas, G.E.; Bariamis, S.E.; Athanassopoulos, C.M.; Drainas, D.; et al. Effect of an all-trans-retinoic acid conjugate with spermine on viability of human prostate cancer and endothelial cells in vitro and angiogenesis in vivo. Eur. J. Pharmacol. 2013, 21, 122–130. [Google Scholar] [CrossRef]
  87. Petrie, K.; Urban-Wójciuk, Z.; Sbirkov, Y.; Graham, A.; Hamann, A.; Brown, G. Retinoic acid receptor γ is a therapeutically targetable driver of growth and survival in prostate cancer. Cancer Rep. 2020, 3, e1284. [Google Scholar] [CrossRef] [PubMed]
  88. Liu, Z.; Ren, G.; Shangguan, C.; Guo, L.; Dong, Z.; Li, Y.; Zhang, W.; Zhao, L.; Hou, P.; Zhang, Y.; et al. ATRA Inhibits the Proliferation of DU145 Prostate Cancer Cells through Reducing the Methylation Level of HOXB13 Gene. PLoS ONE 2012, 7, e40943. [Google Scholar] [CrossRef] [PubMed]
  89. Menschikowski, M.; Hagelgans, A.; Tiebel, O.; Vogel, M.; Eisenhofer, G.; Siegert, G. Regulation of thrombomodulin expression in prostate cancer cells. Cancer Lett. 2012, 322, 177–184. [Google Scholar] [CrossRef] [PubMed]
  90. Tsagozis, P.; Augsten, M.; Pisa, P. All trans-retinoic acid abrogates the pro-tumorigenic phenotype of prostate cancer tumor-associated macrophages. Int. Immunophamracol. 2014, 23, 8–13. [Google Scholar] [CrossRef] [PubMed]
  91. Lin, E.; Chen, M.-C.; Huang, C.-Y.; Hsu, S.-L.; Huang, W.J.; Lin, M.-S.; Wu, J.C.-H.; Lin, H. All-Trans Retinoic Acid Induces DU145 Cell Cycle Arrest through Cdk5 Activation. Cell. Physiol. Biochem. 2014, 33, 1620–1630. [Google Scholar] [CrossRef]
  92. Seed, R.I.; Taurozzi, A.J.; Wilcock, D.J.; Nappo, G.; Erb, H.H.; Read, M.L.; Gurney, M.; Archer, L.K.; Ito, S.; Rumsby, M.G.; et al. The putative tumour suppressor protein Latexin is secreted by prostate luminal cells and is downregulated in malignancy. Sci. Rep. 2019, 9, 5120. [Google Scholar] [CrossRef]
  93. Chen, M.-C.; Hsu, S.-L.; Lin, H.; Yang, T.-Y. Inhibitory Effects of Retinol Are Greater than Retinoic Acid on the Growth and Adhesion of Human Refractory Cancer Cells. Biol. Pharm. Bull. 2016, 39, 636–640. [Google Scholar]
  94. Sha, J.; Pan, J.; Ping, P.; Xuan, H.; Li, D.; Bo, J.; Liu, D.; Huang, Y. Synergistic effect and mechanism of vitamin A and vitamin D on inducing apoptosis of prostate cancer cells. Mol. Biol. Rep. 2013, 40, 2763–2768. [Google Scholar] [CrossRef] [PubMed]
  95. Chen, H.-Y.; Huang, S.-M.; Yang, C.-M.; Hu, M.-L. Diverse Effects of β-Carotene on Secretion and Expression of VEGF in Human Hepatocarcinoma and Prostate Tumor Cells. Molecules 2012, 17, 3981–3988. [Google Scholar] [CrossRef] [PubMed]
  96. Rafi, M.M.; Kanakasabai, S.; Gokarn, S.V.; Krueger, E.G.; Bright, J.J. Dietary Lutein Modulates Growth and Survival Genes in Prostate Cancer Cells. J. Med. Food 2014, 18, 173–181. [Google Scholar] [CrossRef]
  97. Yang, Y.; Fuentes, F.; Shu, L.; Wang, C.; Pung, D.; Li, W.; Zhang, C.; Guo, Y.; Kong, A.-N. Epigenetic CpG Methylation of the Promoter and Reactivation of the Expression of GSTP1 by Astaxanthin in Human Prostate LNCaP Cells. AAPS J. 2016, 19, 421–430. [Google Scholar] [CrossRef]
  98. Festuccia, C.; Mancini, A.; Gravina, G.L.; Scarsella, L.; Llorens, S.; Alonso, G.L.; Tatone, C.; Di Cesare, E.; Jannini, E.A.; Lenzi, A. Antitumor Effects of Saffron-Derived Carotenoids in Prostate Cancer Cell Models. BioMed Res. Int. 2014, 2014, 1–12. [Google Scholar] [CrossRef]
  99. Kaighn, M.; Narayan, K.; Ohnuki, Y.; Lechner, J.; Jones, L.W. Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Investig. Urol. 1979, 17, 16–23. [Google Scholar]
  100. van Bokhoven, A.; Varella-Garcia, M.; Korch, C.; Johannes, W.; Smith, E.; Miller, H.; Nordeen, S.; Miller, G.; Lucia, M. Molecular characterization of human prostate carcinoma cell lines. Prostate 2003, 57, 205–225. [Google Scholar] [CrossRef] [PubMed]
  101. Horoszewicz, J.; Leong, S.; Kawinski, E.; Karr, J.; Rosenthal, H.; Chu, T. LNCaP Model of Human Prostatic Carcinoma. Cancer Res. 1983, 43, 1809–1818. [Google Scholar] [PubMed]
  102. Alimirah, F.; Chen, J.; Basrawala, Z.; Xin, H.; Choubey, D. DU-145 and PC-3 human prostate cancer cell lines express androgen receptor: Implications for the androgen receptor functions and regulation. FEBS Lett. 2006, 580, 2294–2300. [Google Scholar] [CrossRef] [PubMed]
  103. Tai, S.; Sun, Y.; Squires, J.; Zhang, H.; Oh, W.; Liang, C.-Z.; Huang, J. PC3 is a cell line characteristic of prostatic small cell carcinoma. Prostate 2011, 71, 1668–1679. [Google Scholar] [CrossRef]
  104. Patel, M.; Vadlapatla, R.K.; Shah, S.; Mitra, A.K. Molecular expression and functional activity of sodium dependent multivitamin transporter in human prostate cancer cells. Int. J. Pharm. 2012, 436, 324–331. [Google Scholar] [CrossRef]
  105. Chan, J.M.; Weinberg, V.; Magbanua, M.J.; Sosa, E.; Simko, J.; Shinohara, K.; Federman, S.; Mattie, M.; Hughes-Fulford, M.; Haqq, C.; et al. Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer. Cancer Causes Control 2011, 22, 141–150. [Google Scholar] [CrossRef] [PubMed]
  106. Magbanua, M.J.M.; Roy, R.; Sosa, E.V.; Weinberg, V.; Federman, S.; Mattie, M.D.; Hughes-Fulford, M.; Simko, J.; Shinohara, K.; Haqq, C.M.; et al. Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation. PLoS ONE 2011, 6, e24004. [Google Scholar] [CrossRef]
  107. Lekchnov, E.A.; Amelina, E.V.; Bryzgunova, O.E.; Zaporozhchenko, I.A.; Konoshenko, M.Y.; Yarmoschuk, S.V.; Murashov, I.S.; Pashkovskaya, O.A.; Gorizkii, A.M.; Zheravin, A.A.; et al. Searching for the Novel Specific Predictors of Prostate Cancer in Urine: The Analysis of 84 miRNA Expression. Int. J. Med. Sci. 2018, 19, 4088. [Google Scholar] [CrossRef]
  108. Moran, N.E.; Thomas-Ahner, J.M.; Fleming, J.L.; McElroy, J.P.; Mehl, R.; Grainger, E.M.; Riedl, K.M.; Toland, A.E.; Schwartz, S.J.; Clinton, S.K. Single Nucleotide Polymorphisms in β-Carotene Oxygenase 1 are Associated with Plasma Lycopene Responses to a Tomato-Soy Juice Intervention in Men with Prostate Cancer. J. Nutr. 2019, 149, 381–397. [Google Scholar] [CrossRef] [PubMed]
  109. Beynon, R.; Richmond, R.; Santos Ferreira, D.; Ness, A.; May, M.; Smith, G.; Vincent, E.; Adams, C.; Ala-Korpela, M.; Würtz, P. Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial. Int. J. Cancer 2019, 15, 1918–1928. [Google Scholar] [CrossRef]
  110. Talvas, J.; Caris-Veyrat, C.; Guy, L.; Rambeau, M.; Lyan, B.; Minet-Quinard, R.; Lobaccaro, J.-M.A.; Vasson, M.-P.; Georgé, S.; Mazur, A. Differential effects of lycopene consumed in tomato paste and lycopene in the form of a purified extract on target genes of cancer prostatic cells. Am. J. Clin. Nutr. 2010, 91, 1716–1724. [Google Scholar] [CrossRef]
  111. Neuhouser, M.L.; Barnett, M.J.; Kristal, A.R.; Ambrosone, C.; King, I.B.; Thornquist, M.; Goodman, G.G. Dietary supplement use and prostate cancer risk in the Carotene and Retinol Efficacy Trial. Cancer Epidemiol. Biomark. Prev. 2009, 18, 2202–2206. [Google Scholar] [CrossRef]
  112. Schenk, J.M.; Riboli, E.; Chatterjee, N.; Leitzmann, M.F.; Ahn, J.; Albanes, D.; Reding, D.J.; Wang, Y.; Friesen, M.D.; Hayes, R.B.; et al. Serum retinol and prostate cancer risk: A nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol. Biomark. Prev. 2009, 18, 1227–1231. [Google Scholar] [CrossRef] [PubMed]
  113. Karppi, J.; Kurl, S.; Laukkanen, J.A.; Kauhanen, J. Serum β-Carotene in Relation to Risk of Prostate Cancer: The Kuopio Ischaemic Heart Disease Risk Factor Study. Nutr. Cancer 2012, 64, 361–367. [Google Scholar] [CrossRef] [PubMed]
  114. Virtamo, J.; Taylor, P.R.; Kontto, J.; Männistö, S.; Utriainen, M.; Weinstein, S.J.; Huttunen, J.; Albanes, D. Effects of α-tocopherol and β-carotene supplementation on cancer incidence and mortality: 18-year postintervention follow-up of the Alpha-tocopherol, Beta-carotene Cancer Prevention Study. Int. J. Cancer 2014, 1, 178–185. [Google Scholar] [CrossRef]
  115. Nordström, T.; Van Blarigan, E.L.; Ngo, V.; Roy, R.; Weinberg, V.; Song, X.; Simko, J.; Carroll, P.R.; Chan, J.M.; Paris, P.L. Associations between circulating carotenoids, genomic instability and the risk of high-grade prostate cancer. Prostate 2016, 76, 339–348. [Google Scholar] [CrossRef]
  116. Choi, H.D.; Youn, Y.K.; Shin, W.G. Positive Effects of Astaxanthin on Lipid Profiles and Oxidative Stress in Overweight Subjects. Plant Foods Hum. Nutr. 2011, 66, 363–369. [Google Scholar] [CrossRef]
  117. Sun, S.-Q.; Zhao, Y.-X.; Li, S.-Y.; Qiang, J.-W.; Ji, Y.-Z. Anti-Tumor Effects of Astaxanthin by Inhibition of the Expression of STAT3 in Prostate Cancer. Mar. Drugs 2020, 18, 415. [Google Scholar] [CrossRef]
  118. Ni, X.; Yu, H.; Wang, S.; Zhang, C.; Shen, S. Astaxanthin Inhibits PC-3 Xenograft Prostate Tumor Growth in Nude Mice. Mar. Drugs 2017, 15, 66. [Google Scholar] [CrossRef]
  119. Formosa, A.; Markert, E.K.; Lena, A.M.; Italiano, D.; Finazzi-Agro, E.; Levine, A.J.; Bernardini, S.; Garabadgiu, A.V.; Melino, G.; Candi, E. MicroRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 locus, regulate proliferation, apoptosis, migration and invasion in metastatic prostate cancer cells. Oncogene 2013, 33, 5173–5182. [Google Scholar] [CrossRef] [PubMed]
  120. Katsumata, T.; Ishibashi, T.; Kyle, D. A sub-chronic toxicity evaluation of a natural astaxanthin-rich carotenoid extract of Paracoccus carotinifaciens in rats. Toxicol. Rep. 2014, 1, 582–588. [Google Scholar] [CrossRef]
  121. Satomi, Y. Fucoxanthin induces GADD45A expression and G1 arrest with SAPK/JNK activation in LNCap human prostate cancer cells. Anticancer Res. 2012, 32, 807–813. [Google Scholar] [PubMed]
  122. Rezaeeyan, Z.; Safarpour, A.; Amoozegar, M.A.; Babavalian, H.; Tebyanian, H.; Shakeri, F. High carotenoid production by a halotolerant bacterium, Kocuria sp. strain QWT-12 and anticancer activity of its carotenoid. EXCLI J. 2017, 16, Doc840. [Google Scholar]
  123. Altavilla, D.; Bitto, A.; Polito, F.; Irrera, N.; Marini, H.; Arena, S.; Favilla, V.; Squadrito, F.; Morgia, G.; Minutoli, L. The combination of Serenoa repens, selenium and lycopene is more effective than serenoa repens alone to prevent hormone dependent prostatic growth. J. Urol. 2011, 186, 1524–1529. [Google Scholar] [CrossRef]
  124. Geavlete, P.; Multescu, R.; Geavlete, B. Serenoa repens extract in the treatment of benign prostatic hyperplasia. Ther. Adv. Urol. 2011, 3, 193–198. [Google Scholar] [CrossRef]
  125. Minutoli, L.; Altavilla, D.; Marini, H.; Rinaldi, M.; Irrera, N.; Pizzino, G.; Bitto, A.; Arena, S.; Cimino, S.; Squadrito, F.; et al. Inhibitors of apoptosis proteins in experimental benign prostatic hyperplasia: Effects of serenoa repens, selenium and lycopene. J. Biomed. Sci. 2014, 21, 19. [Google Scholar] [CrossRef] [PubMed]
  126. Rodríguez-Berriguete, G.; Fraile, B.; de Bethencourt, F.R.; Prieto-Folgado, A.; Bartolome, N.; Nuñez, C.; Prati, B.; Martínez-Onsurbe, P.; Olmedilla, G.; Paniagua, R.; et al. Role of IAPs in prostate cancer progression: Immunohistochemical study in normal and pathological (benign hyperplastic, prostatic intraepithelial neoplasia and cancer) human prostate. BMC Cancer 2010, 10, 18. [Google Scholar] [CrossRef]
  127. Wertz, K. Lycopene effects contributing to prostate health. Nutr. Cancer 2009, 61, 775–783. [Google Scholar] [CrossRef]
  128. Ford, N.A.; Clinton, S.K.; von Lintig, J.; Wyss, A.; Erdman, J.W., Jr. Loss of carotene-9’,10’-monooxygenase expression increases serum and tissue lycopene concentrations in lycopene-fed mice. J. Nutr. 2010, 140, 2134–2138. [Google Scholar] [CrossRef] [PubMed]
  129. Kumar, N.B.; Besterman-Dahan, K.; Kang, L.; Pow-Sang, J.; Xu, P.; Allen, K.; Riccardi, D.; Krischer, J.P. Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy. Clin. Med. Insights Urol. 2008, 1, 1–14. [Google Scholar] [CrossRef] [PubMed]
  130. Boileau, T.W.-M.; Clinton, S.; Zaripheh, S.; Monaco, M.H.; Donovan, S.M.; Erdman, J.W. Testosterone and food restriction modulate hepatic lycopene isomer concentrations in male F344 rats. J. Nutr. 2001, 48, 1746–1752. [Google Scholar] [CrossRef] [PubMed]
  131. Qiu, X.; Yuan, Y.; Vaishnav, A.; Tessel, M.A.; Nonn, L.; van Breemen, R.B. Effects of lycopene on protein expression in human primary prostatic epithelial cells. Cancer Prev. Res. 2013, 6, 419–427. [Google Scholar] [CrossRef] [PubMed]
  132. GSTP1 Glutathione S-Transferase pi 1 [Homo Sapiens (Human)]. Available online: https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=2950 (accessed on 24 August 2019).
  133. Linnewiel, K.; Ernst, H.; Caris-Veyrat, C.; Ben-Dor, A.; Kampf, A.; Salman, H.; Danilenko, M.; Levy, J.; Sharoni, Y. Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system. Free Radic. Biol. Med. 2009, 47, 659–667. [Google Scholar] [CrossRef] [PubMed]
  134. Du, C.; Guo, Y.; Cheng, Y.; Han, M.; Zhang, W.; Qian, H. Torulene and torularhodin, protects human prostate stromal cells from hydrogen peroxide-induced oxidative stress damage through the regulation of Bcl-2/Bax mediated apoptosis. Free Radic. Res. 2017, 51, 113–123. [Google Scholar] [CrossRef] [PubMed]
  135. Meng, H.-Z.; Ni, X.-F.; Yu, H.-N.; Wang, S.-S.; Shen, S.-R. Effects of astaxanthin on oxidative stress induced by Cu2+ in prostate cells. J. Zhejiang Univ. 2017, 18, 161–171. [Google Scholar] [CrossRef]
  136. Murashima, A.; Kishigami, S.; Thomson, A.; Yamada, G. Androgens and mammalian male reproductive tract development. Biochim. Biophys. Acta Gene Regul. Mech. 2015, 1849, 163–170. [Google Scholar] [CrossRef]
  137. Bryant, S.L.; Francis, J.C.; Lokody, I.B.; Wang, H.; Risbridger, G.P.; Loveland, K.L.; Swain, A. Sex specific retinoic acid signaling is required for the initiation of urogenital sinus bud development. Dev. Biol. 2014, 395, 209–217. [Google Scholar] [CrossRef] [PubMed]
  138. Rivera-Gonzalez, G.C.; Droop, A.P.; Rippon, H.J.; Tiemann, K.; Pellacani, D.; Georgopoulos, L.J.; Maitland, N.J. Retinoic acid and androgen receptors combine to achieve tissue specific control of human prostatic transglutaminase expression:a novel regulatory network with broader significance. Nucleic Acids Res. 2012, 40, 4825–4840. [Google Scholar] [CrossRef] [PubMed]
  139. Cai, K.; Gudas, L.J. Retinoic acid receptors and GATA transcription factors activate the transcription of the human lecithin:retinol acyltransferase gene. Int. J. Biochem. Cell Biol. 2009, 41, 546–553. [Google Scholar] [CrossRef] [PubMed]
  140. Fontanelli, B.A.F.; Chuffa, L.G.A.; Teixeira, G.R.; Amorim, J.P.A.; Mendes, L.O.; Pinheiro, P.F.F.; Kurokawa, C.S.; Pereira, S.; Fávaro, W.J.; Martins, O.A.; et al. Chronic ethanol consumption alters all-trans-retinoic acid concentration and expression of their receptors on the prostate: A possible link between alcoholism and prostate damage. Alcohol. Clin. Exp. Res. 2013, 1, 49–56. [Google Scholar] [CrossRef]
  141. Fioruci-Fontanelli, B.A.; Chuffa, L.G.A.; Mendes, L.O.; Pinheiro, P.F.F.; Justulin, L.A., Jr.; Felisbino, S.L.; Martinez, F.E. Ethanol modulates the synthesis and catabolism of retinoic acid in the rat prostate. Reprod. Toxicol. 2015, 53, 1–9. [Google Scholar] [CrossRef]
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The Potential of Sun-Dried Grape Pomace as a Multi-Functional Ingredient for Herbal Infusion: Effects of Brewing Parameters on Composition and Bioactivity
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Antioxidants Such as Flavonoids and Carotenoids in the Diet of Bogor, Indonesia Residents
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