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Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2019) | Viewed by 161809

Special Issue Editors

Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
Interests: noncoding RNAs; micro-RNAs; prostate cancer; nanotechnological delivery of anticancer drugs and nucleic acids; diagnostic markers in cancer; Urotensin II receptor; next-generation sequencing; predictive markers of response; circulating tumor cells
Special Issues, Collections and Topics in MDPI journals
Department of Biochemistry, Biophysics and General Pathology, School of Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: aging; oxidative stress; nitric oxide; endothelial cells; endothelial progenitor cells; angiogenesis; inflammation; cell senescence; apoptosis; atherosclerosis; diabetes, endothelial dysfunction, sirtuins and cardiovascular disease; natural products; betaines; health; bioactive compounds; free radicals; antioxidants; ergothioneine; cell cycle; cancer-related biochemical pathways; cell proliferation; senescence; cancer cell death; epigenetic regulation; sirtuins and cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The mechanisms of cell death have a pivotal role in the determination of the fate of normal and cancer cells in multicellular organism. The disruption of these mechanisms is at the core of the development of inflammatory and tumor diseases and knowledge of the molecular components altered in specific illnesses can be useful in the design of new therapeutic strategies for the treatment of human cancers as well as of inflammatory diseases. Two of the most known cell death mechanisms are apoptosis and autophagy, which are differently-involved in the regulation of tumor cell proliferation and metastatization. These mechanisms are often opposite, and autophagy is described as an escape mechanism from apoptotic occurrence, representing a protective effect of tumor cells to anti-cancer agents or hypoxic conditions, both of which are deleterious for cancer progression. On the other hand, some anti-cancer agents can induce autophagy during the repression of tumor proliferation. In this way, autophagy can become a marker of cancer response to treatment. The existence of specific tumor conditions can determine the functional role of autophagy in cancer tissues. The interaction between autophagy and apoptosis occurs through the cross talk of respective molecular mechanisms that are able to influence each other in a tunable way. It is also emerging a role for apoptosis and autophagy in the regulation of normal tissue development and differentiation. Therefore, apoptosis and autophagy regulate also the physiological mechanisms of several organs (i.e., liver and ovary) and are involved in the occurrence of several diseases based upon either a development defect or a chronic inflammatory status. The intervention on the programmed cell death with specific agents can be a new strategy for the treatment of this kind of diseases.

This issue of the International Journal of Molecular Sciences will focus on recent advances in “Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases”, including new insights into the molecular mechanisms of apoptosis, autophagy and other programmed cell death mechanisms (i.e., senescence) and their correlations with the control of cancer growth and metastatization and tissue development and inflammation. Moreover, emerging data on natural or synthetic modulators of apoptosis and autophagy, in relation to new therapeutic strategies, are welcome.

Prof. Dr. Michele Caraglia
Prof. Dr. Maria Luisa Balestrieri
Guest Editors

Manuscript Submission Information

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Keywords

  • apoptosis
  • autophagy
  • cancer
  • miRNA
  • long non-coding RNAs
  • senescence
  • inflammation
  • therapeutics

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Published Papers (20 papers)

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Research

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15 pages, 1890 KiB  
Article
RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis
by Praveen Manivannan, Vidita Reddy, Sushovita Mukherjee, Kirsten Neytania Clark and Krishnamurthy Malathi
Int. J. Mol. Sci. 2019, 20(14), 3535; https://doi.org/10.3390/ijms20143535 - 19 Jul 2019
Cited by 13 | Viewed by 3758
Abstract
Apoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2′–5′ oligoadenylate synthetase/RNase L pathway results in activation of RNase L in response to double stranded RNA and cleaves [...] Read more.
Apoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2′–5′ oligoadenylate synthetase/RNase L pathway results in activation of RNase L in response to double stranded RNA and cleaves diverse RNA substrates to amplify interferon induction and promote apoptosis. Here we show that RNase L induces expression of Death-associated protein kinase-Related Apoptosis-inducing protein Kinase 1 (DRAK1), a member of the death-associated protein kinase family and interferon-signaling pathway is required for induction. Overexpression of DRAK1 triggers apoptosis in the absence of RNase L activation by activating c-Jun N-terminal kinase (JNK), translocation of BCL2 Associated X (Bax) to the mitochondria accompanied by cytochrome C release and loss of mitochondrial membrane potential promoting cleavage of caspase 3 and Poly(ADP-Ribose) Polymerase 1 (PARP). Inhibitors of JNK and caspase 3 promote survival of DRAK1 overexpressing cells demonstrating an important role of JNK signaling pathway in DRAK1-mediated apoptosis. DRAK1 mutant proteins that lack kinase activity or nuclear localization fail to induce apoptosis highlighting the importance of cellular localization and kinase function in promoting cell death. Our studies identify DRAK1 as a mediator of RNase L-induced apoptosis. Full article
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18 pages, 2406 KiB  
Article
Effects of Long-Term Citrate Treatment in the PC3 Prostate Cancer Cell Line
by Carmen Caiazza, Massimo D’Agostino, Fabiana Passaro, Deriggio Faicchia, Massimo Mallardo, Simona Paladino, Giovanna Maria Pierantoni and Donatella Tramontano
Int. J. Mol. Sci. 2019, 20(11), 2613; https://doi.org/10.3390/ijms20112613 - 28 May 2019
Cited by 18 | Viewed by 5518
Abstract
Acute administration of a high level of extracellular citrate displays an anti-proliferative effect on both in vitro and in vivo models. However, the long-term effect of citrate treatment has not been investigated yet. Here, we address this question in PC3 cells, a prostate-cancer-derived [...] Read more.
Acute administration of a high level of extracellular citrate displays an anti-proliferative effect on both in vitro and in vivo models. However, the long-term effect of citrate treatment has not been investigated yet. Here, we address this question in PC3 cells, a prostate-cancer-derived cell line. Acute administration of high levels of extracellular citrate impaired cell adhesion and inhibited the proliferation of PC3 cells, but surviving cells adapted to grow in the chronic presence of 20 mM citrate. Citrate-resistant PC3 cells are significantly less glycolytic than control cells. Moreover, they overexpress short-form, citrate-insensitive phosphofructokinase 1 (PFK1) together with full-length PFK1. In addition, they show traits of mesenchymal-epithelial transition: an increase in E-cadherin and a decrease in vimentin. In comparison with PC3 cells, citrate-resistant cells display morphological changes that involve both microtubule and microfilament organization. This was accompanied by changes in homeostasis and the organization of intracellular organelles. Thus, the mitochondrial network appears fragmented, the Golgi complex is scattered, and the lysosomal compartment is enlarged. Interestingly, citrate-resistant cells produce less total ROS but accumulate more mitochondrial ROS than control cells. Consistently, in citrate-resistant cells, the autophagic pathway is upregulated, possibly sustaining their survival. In conclusion, chronic administration of citrate might select resistant cells, which could jeopardize the benefits of citrate anticancer treatment. Full article
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14 pages, 2623 KiB  
Article
Silybin-Induced Apoptosis Occurs in Parallel to the Increase of Ceramides Synthesis and miRNAs Secretion in Human Hepatocarcinoma Cells
by Silvia Zappavigna, Daniela Vanacore, Stefania Lama, Nicoletta Potenza, Aniello Russo, Pasquale Ferranti, Marcello Dallio, Alessandro Federico, Carmelina Loguercio, Pasquale Sperlongano, Michele Caraglia and Paola Stiuso
Int. J. Mol. Sci. 2019, 20(9), 2190; https://doi.org/10.3390/ijms20092190 - 03 May 2019
Cited by 22 | Viewed by 2879
Abstract
Silybin is a flavonolignan extracted from Silybum marianum (milk thistle) with hepatoprotective, antioxidant, and anti-inflammatory activity. Several studies have shown that silybin is highly effective to prevent and treat different types of cancer and that its antitumor mechanisms involve the arrest of the [...] Read more.
Silybin is a flavonolignan extracted from Silybum marianum (milk thistle) with hepatoprotective, antioxidant, and anti-inflammatory activity. Several studies have shown that silybin is highly effective to prevent and treat different types of cancer and that its antitumor mechanisms involve the arrest of the cell cycle and/or apoptosis. An MTT assay was performed to study cell viability, lipid peroxidation, extracellular NO production, and scavenger enzyme activity were studied by Thiobarbituric Acid-Reactive Species (TBARS) assay, NO assay, and MnSOD assay, respectively. Cell cycle and apoptosis analysis were performed by FACS. miRNA profiling were evaluated by real time PCR. In this study, we demonstrated that Silybin induced growth inhibition blocking the Hepg2 cells in G1 phase of cell cycle and activating the process of programmed cell death. Moreover, the antiproliferative effects of silybin were paralleled by a strong increase of the number of ceramides involved in the modulation of miRNA secretion. In particular, after treatment with silybin, miR223-3p and miR16-5p were upregulated, while miR-92-3p was downregulated (p < 0.05). In conclusion, our results suggest that silybin-Induced apoptosis occurs in parallel to the increase of ceramides synthesis and miRNAs secretion in HepG2 cells. Full article
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18 pages, 2184 KiB  
Article
Capsaicin Targets Lipogenesis in HepG2 Cells Through AMPK Activation, AKT Inhibition and PPARs Regulation
by Alicia Bort, Belén G. Sánchez, Pedro A. Mateos-Gómez, Inés Díaz-Laviada and Nieves Rodríguez-Henche
Int. J. Mol. Sci. 2019, 20(7), 1660; https://doi.org/10.3390/ijms20071660 - 03 Apr 2019
Cited by 45 | Viewed by 7100
Abstract
Obesity, a major risk factor for chronic diseases such as type 2 diabetes (T2D), represents a serious primary health problem worldwide. Dietary habits are of special interest to prevent and counteract the obesity and its associated metabolic disorders, including lipid steatosis. Capsaicin, a [...] Read more.
Obesity, a major risk factor for chronic diseases such as type 2 diabetes (T2D), represents a serious primary health problem worldwide. Dietary habits are of special interest to prevent and counteract the obesity and its associated metabolic disorders, including lipid steatosis. Capsaicin, a pungent compound of chili peppers, has been found to ameliorate diet-induced obesity in rodents and humans. The purpose of this study was to examine the effect of capsaicin on hepatic lipogenesis and to delineate the underlying signaling pathways involved, using HepG2 cells as an experimental model. Cellular neutral lipids, stained with BODIPY493/503, were quantified by flow cytometry, and the protein expression and activity were determined by immunoblotting. Capsaicin reduced basal neutral lipid content in HepG2 cells, as well that induced by troglitazone or by oleic acid. This effect of capsaicin was prevented by dorsomorphin and GW9662, pharmacological inhibitors of AMPK and PPARγ, respectively. In addition, capsaicin activated AMPK and inhibited the AKT/mTOR pathway, major regulators of hepatic lipogenesis. Furthermore, capsaicin blocked autophagy and increased PGC-1α protein. These results suggest that capsaicin behaves as an anti-lipogenic compound in HepG2 cells. Full article
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8 pages, 1322 KiB  
Communication
Upregulated Autophagy in Calcific Aortic Valve Stenosis Confers Protection of Valvular Interstitial Cells
by Miguel Carracedo, Oscar Persson, Peter Saliba-Gustafsson, Gonzalo Artiach, Ewa Ehrenborg, Per Eriksson, Anders Franco-Cereceda and Magnus Bäck
Int. J. Mol. Sci. 2019, 20(6), 1486; https://doi.org/10.3390/ijms20061486 - 25 Mar 2019
Cited by 18 | Viewed by 3534
Abstract
Autophagy serves as a cell survival mechanism which becomes dysregulated under pathological conditions and aging. Aortic valve thickening and calcification causing left ventricular outflow obstruction is known as calcific aortic valve stenosis (CAVS). CAVS is a chronic and progressive disease which increases in [...] Read more.
Autophagy serves as a cell survival mechanism which becomes dysregulated under pathological conditions and aging. Aortic valve thickening and calcification causing left ventricular outflow obstruction is known as calcific aortic valve stenosis (CAVS). CAVS is a chronic and progressive disease which increases in incidence and severity with age. Currently, no medical treatment exists for CAVS, and the role of autophagy in the disease remains largely unexplored. To further understand the role of autophagy in the progression of CAVS, we analyzed expression of key autophagy genes in healthy, thickened, and calcified valve tissue from 55 patients, and compared them with nine patients without significant CAVS, undergoing surgery for aortic regurgitation (AR). This revealed a upregulation in autophagy exclusively in the calcified tissue of CAVS patients. This difference in autophagy between CAVS and AR was explored by LC3 lipidation in valvular interstitial cells (VICs), revealing an upregulation in autophagic flux in CAVS patients. Inhibition of autophagy by bafilomycin-A1 led to a decrease in VIC survival. Finally, treatment of VICs with high phosphate led to an increase in autophagic activity. In conclusion, our data suggests that autophagy is upregulated in the calcified tissue of CAVS, serving as a compensatory and pro-survival mechanism. Full article
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20 pages, 3790 KiB  
Article
The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy
by Mario Joachim Johannes Scheurer, Roman Camillus Brands, Mohamed El-Mesery, Stefan Hartmann, Urs Dietmar Achim Müller-Richter, Alexander Christian Kübler and Axel Seher
Int. J. Mol. Sci. 2019, 20(6), 1306; https://doi.org/10.3390/ijms20061306 - 15 Mar 2019
Cited by 12 | Viewed by 4228
Abstract
Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. [...] Read more.
Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors—Cortisol, MLN4924, QNZ and TPCA1—on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted. Full article
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13 pages, 2216 KiB  
Article
Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR
by Takayuki Ueno, Norikazu Masuda, Shunji Kamigaki, Takashi Morimoto, Shigehira Saji, Shigeru Imoto, Hironobu Sasano and Masakazu Toi
Int. J. Mol. Sci. 2019, 20(4), 984; https://doi.org/10.3390/ijms20040984 - 24 Feb 2019
Cited by 15 | Viewed by 3841
Abstract
Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, [...] Read more.
Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre- and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone. Full article
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13 pages, 2221 KiB  
Article
Role of Klf4 in the Regulation of Apoptosis and Cell Cycle in Rat Granulosa Cells during the Periovulatory Period
by Hyeonhae Choi and Jaesook Roh
Int. J. Mol. Sci. 2019, 20(1), 87; https://doi.org/10.3390/ijms20010087 - 26 Dec 2018
Cited by 19 | Viewed by 4484
Abstract
In the ovary, the luteinizing hormone (LH) surge suppresses the proliferation and induces the luteinization of preovulatory granulosa cells (GCs), which is crucial for the survival of terminally-differentiated GCs. Krüppel-like factor 4 (Klf4) has been shown to play a role in [...] Read more.
In the ovary, the luteinizing hormone (LH) surge suppresses the proliferation and induces the luteinization of preovulatory granulosa cells (GCs), which is crucial for the survival of terminally-differentiated GCs. Krüppel-like factor 4 (Klf4) has been shown to play a role in regulating the cell cycle and apoptosis in various cell types. The rapid induction of Klf4 expressions by LH was observed in preovulatory GCs. To evaluate whether Klf4 affects GC proliferation and survival, primary rat GCs were isolated from pregnant mare serum gonadotropin-primed Sprague–Dawley rat ovaries and transfected with a Klf4 expression vector or Klf4-specific siRNA, followed by determination of the transcript levels of apoptosis-related and cell cycle-related genes. Cell proliferation, viability, and apoptosis were analyzed by BrdU incorporation, a Cell Counting Kit-8 assay, a bioluminescence caspase 3/7 assay, and flow cytometry. LH treatment increased Klf4 mRNA expression in preovulatory GCs. Transcripts of B-cell lymphoma 2 (Bcl-2) and cell cycle promoters (Cyclin D1 and Cyclin D2) decreased, whereas those of the cell cycle inhibitor, p21, increased. Altering the expression of Klf4 by overexpression or knockdown consistently affected the expression of Bcl-2 and Cyclin D1. In agreement with this, Klf4 overexpression reduced cell viability, increased the fraction of apoptotic cells, and arrested cell cycle progression in G1 phase. We conclude that Klf4 increases the susceptibility of preovulatory GCs to apoptosis by down-regulating Bcl-2, and promotes LH-induced cell cycle exit. It appears to be a key regulator induced by the LH surge that determines the fate of GCs in preovulatory follicles during the luteal transition. Full article
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14 pages, 1948 KiB  
Article
Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells
by Félice A. Janser, Olivia Adams, Vanessa Bütler, Anna M. Schläfli, Bastian Dislich, Christian A. Seiler, Dino Kröll, Rupert Langer and Mario P. Tschan
Int. J. Mol. Sci. 2018, 19(10), 3069; https://doi.org/10.3390/ijms19103069 - 08 Oct 2018
Cited by 24 | Viewed by 4054
Abstract
Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 [...] Read more.
Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients. Full article
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Review

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34 pages, 721 KiB  
Review
Mechanism of Apoptosis Induced by Curcumin in Colorectal Cancer
by Nor Isnida Ismail, Iekhsan Othman, Faridah Abas, Nordin H. Lajis and Rakesh Naidu
Int. J. Mol. Sci. 2019, 20(10), 2454; https://doi.org/10.3390/ijms20102454 - 17 May 2019
Cited by 105 | Viewed by 8260
Abstract
Colorectal cancer (CRC) is among the top three cancer with higher incident and mortality rate worldwide. It is estimated that about over than 1.1 million of death and 2.2 million new cases by the year 2030. The current treatment modalities with the usage [...] Read more.
Colorectal cancer (CRC) is among the top three cancer with higher incident and mortality rate worldwide. It is estimated that about over than 1.1 million of death and 2.2 million new cases by the year 2030. The current treatment modalities with the usage of chemo drugs such as FOLFOX and FOLFIRI, surgery and radiotherapy, which are usually accompanied with major side effects, are rarely cured along with poor survival rate and at higher recurrence outcome. This trigger the needs of exploring new natural compounds with anti-cancer properties which possess fewer side effects. Curcumin, a common spice used in ancient medicine was found to induce apoptosis by targeting various molecules and signaling pathways involved in CRC. Disruption of the homeostatic balance between cell proliferation and apoptosis could be one of the promoting factors in colorectal cancer progression. In this review, we describe the current knowledge of apoptosis regulation by curcumin in CRC with regard to molecular targets and associated signaling pathways. Full article
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32 pages, 958 KiB  
Review
p53 at the Crossroads between Different Types of HDAC Inhibitor-Mediated Cancer Cell Death
by Maria Mrakovcic, Johannes Kleinheinz and Leopold F. Fröhlich
Int. J. Mol. Sci. 2019, 20(10), 2415; https://doi.org/10.3390/ijms20102415 - 15 May 2019
Cited by 63 | Viewed by 5766
Abstract
Cancer is a complex genetic and epigenetic-based disease that has developed an armada of mechanisms to escape cell death. The deregulation of apoptosis and autophagy, which are basic processes essential for normal cellular activity, are commonly encountered during the development of human tumors. [...] Read more.
Cancer is a complex genetic and epigenetic-based disease that has developed an armada of mechanisms to escape cell death. The deregulation of apoptosis and autophagy, which are basic processes essential for normal cellular activity, are commonly encountered during the development of human tumors. In order to assist the cancer cell in defeating the imbalance between cell growth and cell death, histone deacetylase inhibitors (HDACi) have been employed to reverse epigenetically deregulated gene expression caused by aberrant post-translational protein modifications. These interfere with histone acetyltransferase- and deacetylase-mediated acetylation of both histone and non-histone proteins, and thereby exert a wide array of HDACi-stimulated cytotoxic effects. Key determinants of HDACi lethality that interfere with cellular growth in a multitude of tumor cells are apoptosis and autophagy, which are either mutually exclusive or activated in combination. Here, we compile known molecular signals and pathways involved in the HDACi-triggered induction of apoptosis and autophagy. Currently, the factors that determine the mode of HDACi-elicited cell death are mostly unclear. Correspondingly, we also summarized as yet established intertwined mechanisms, in particular with respect to the oncogenic tumor suppressor protein p53, that drive the interplay between apoptosis and autophagy in response to HDACi. In this context, we also note the significance to determine the presence of functional p53 protein levels in the cancer cell. The confirmation of the context-dependent function of autophagy will pave the way to improve the benefit from HDACi-mediated cancer treatment. Full article
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17 pages, 1067 KiB  
Review
Regulation of Autophagy by Nuclear GAPDH and Its Aggregates in Cancer and Neurodegenerative Disorders
by Giovanna Butera, Nidula Mullappilly, Francesca Masetto, Marta Palmieri, Maria Teresa Scupoli, Raffaella Pacchiana and Massimo Donadelli
Int. J. Mol. Sci. 2019, 20(9), 2062; https://doi.org/10.3390/ijms20092062 - 26 Apr 2019
Cited by 60 | Viewed by 10094
Abstract
Several studies indicate that the cytosolic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has pleiotropic functions independent of its canonical role in glycolysis. The GAPDH functional diversity is mainly due to post-translational modifications in different amino acid residues or due to protein–protein interactions altering its localization [...] Read more.
Several studies indicate that the cytosolic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has pleiotropic functions independent of its canonical role in glycolysis. The GAPDH functional diversity is mainly due to post-translational modifications in different amino acid residues or due to protein–protein interactions altering its localization from cytosol to nucleus, mitochondria or extracellular microenvironment. Non-glycolytic functions of GAPDH include the regulation of cell death, autophagy, DNA repair and RNA export, and they are observed in physiological and pathological conditions as cancer and neurodegenerative disorders. In disease, the knowledge of the mechanisms regarding GAPDH-mediated cell death is becoming fundamental for the identification of novel therapies. Here, we elucidate the correlation between autophagy and GAPDH in cancer, describing the molecular mechanisms involved and its impact in cancer development. Since autophagy is a degradative pathway associated with the regulation of cell death, we discuss recent evidence supporting GAPDH as a therapeutic target for autophagy regulation in cancer therapy. Furthermore, we summarize the molecular mechanisms and the cellular effects of GAPDH aggregates, which are correlated with mitochondrial malfunctions and can be considered a potential therapeutic target for various diseases, including cancer and neurodegenerative disorders. Full article
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21 pages, 1339 KiB  
Review
Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells
by Mohamed-Reda Benmebarek, Clara Helke Karches, Bruno Loureiro Cadilha, Stefanie Lesch, Stefan Endres and Sebastian Kobold
Int. J. Mol. Sci. 2019, 20(6), 1283; https://doi.org/10.3390/ijms20061283 - 14 Mar 2019
Cited by 244 | Viewed by 25973
Abstract
Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by [...] Read more.
Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor’s individual components—scFv, spacer domain, and costimulatory domains—and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects. Full article
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27 pages, 6155 KiB  
Review
Targeting Autophagy to Overcome Human Diseases
by Maria Condello, Evelin Pellegrini, Michele Caraglia and Stefania Meschini
Int. J. Mol. Sci. 2019, 20(3), 725; https://doi.org/10.3390/ijms20030725 - 08 Feb 2019
Cited by 82 | Viewed by 9184
Abstract
Autophagy is an evolutionarily conserved cellular process, through which damaged organelles and superfluous proteins are degraded, for maintaining the correct cellular balance during stress insult. It involves formation of double-membrane vesicles, named autophagosomes, that capture cytosolic cargo and deliver it to lysosomes, where [...] Read more.
Autophagy is an evolutionarily conserved cellular process, through which damaged organelles and superfluous proteins are degraded, for maintaining the correct cellular balance during stress insult. It involves formation of double-membrane vesicles, named autophagosomes, that capture cytosolic cargo and deliver it to lysosomes, where the breakdown products are recycled back to cytoplasm. On the basis of degraded cell components, some selective types of autophagy can be identified (mitophagy, ribophagy, reticulophagy, lysophagy, pexophagy, lipophagy, and glycophagy). Dysregulation of autophagy can induce various disease manifestations, such as inflammation, aging, metabolic diseases, neurodegenerative disorders and cancer. The understanding of the molecular mechanism that regulates the different phases of the autophagic process and the role in the development of diseases are only in an early stage. There are still questions that must be answered concerning the functions of the autophagy-related proteins. In this review, we describe the principal cellular and molecular autophagic functions, selective types of autophagy and the main in vitro methods to detect the role of autophagy in the cellular physiology. We also summarize the importance of the autophagic behavior in some diseases to provide a novel insight for target therapies. Full article
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102 pages, 1639 KiB  
Review
Diverse Functions of Autophagy in Liver Physiology and Liver Diseases
by Po-Yuan Ke
Int. J. Mol. Sci. 2019, 20(2), 300; https://doi.org/10.3390/ijms20020300 - 13 Jan 2019
Cited by 79 | Viewed by 13759
Abstract
Autophagy is a catabolic process by which eukaryotic cells eliminate cytosolic materials through vacuole-mediated sequestration and subsequent delivery to lysosomes for degradation, thus maintaining cellular homeostasis and the integrity of organelles. Autophagy has emerged as playing a critical role in the regulation of [...] Read more.
Autophagy is a catabolic process by which eukaryotic cells eliminate cytosolic materials through vacuole-mediated sequestration and subsequent delivery to lysosomes for degradation, thus maintaining cellular homeostasis and the integrity of organelles. Autophagy has emerged as playing a critical role in the regulation of liver physiology and the balancing of liver metabolism. Conversely, numerous recent studies have indicated that autophagy may disease-dependently participate in the pathogenesis of liver diseases, such as liver hepatitis, steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma. This review summarizes the current knowledge on the functions of autophagy in hepatic metabolism and the contribution of autophagy to the pathophysiology of liver-related diseases. Moreover, the impacts of autophagy modulation on the amelioration of the development and progression of liver diseases are also discussed. Full article
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21 pages, 972 KiB  
Review
The Ambivalent Function of YAP in Apoptosis and Cancer
by Xianbin Zhang, Ahmed Abdelrahman, Brigitte Vollmar and Dietmar Zechner
Int. J. Mol. Sci. 2018, 19(12), 3770; https://doi.org/10.3390/ijms19123770 - 27 Nov 2018
Cited by 40 | Viewed by 8684
Abstract
Yes-associated protein, a core regulator of the Hippo-YAP signaling pathway, plays a vital role in inhibiting apoptosis. Thus, several studies and reviews suggest that yes-associated protein is a good target for treating cancer. Unfortunately, more and more evidence demonstrates that this protein is [...] Read more.
Yes-associated protein, a core regulator of the Hippo-YAP signaling pathway, plays a vital role in inhibiting apoptosis. Thus, several studies and reviews suggest that yes-associated protein is a good target for treating cancer. Unfortunately, more and more evidence demonstrates that this protein is also an essential contributor of p73-mediated apoptosis. This questions the concept that yes-associated protein is always a good target for developing novel anti-cancer drugs. Thus, the aim of this review was to evaluate the clinical relevance of yes-associated protein for cancer pathophysiology. This review also summarized the molecules, processes and drugs, which regulate Hippo-YAP signaling and discusses their effect on apoptosis. In addition, issues are defined, which should be addressed in the future in order to provide a solid basis for targeting the Hippo-YAP signaling pathway in clinical trials. Full article
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16 pages, 425 KiB  
Review
An Apoptotic and Endosymbiotic Explanation of the Warburg and the Inverse Warburg Hypotheses
by Szymon Kaczanowski, Joanna Klim and Urszula Zielenkiewicz
Int. J. Mol. Sci. 2018, 19(10), 3100; https://doi.org/10.3390/ijms19103100 - 10 Oct 2018
Cited by 8 | Viewed by 4505
Abstract
Otto Warburg, a Nobel prize winner, observed that cancer cells typically “switch” from aerobic to anaerobic respiration. He hypothesized that mitochondrial damage induces neoplastic transformation. In contrast, pathological aging is observed mainly in neuron cells in neurodegenerative diseases. Oxidative respiration is particularly active [...] Read more.
Otto Warburg, a Nobel prize winner, observed that cancer cells typically “switch” from aerobic to anaerobic respiration. He hypothesized that mitochondrial damage induces neoplastic transformation. In contrast, pathological aging is observed mainly in neuron cells in neurodegenerative diseases. Oxidative respiration is particularly active in neurons. There is inverse comorbidity between cancer and neurodegenerative diseases. This led to the creation of the “inverse Warburg hypothesis”, according to which excessive mitochondrial activity induces pathological aging. The findings of our studies suggest that both the Warburg effect and the “inverse Warburg hypothesis” can be elucidated by the activation or suppression of apoptosis through oxidative respiration. The key outcome of our phylogenetic studies was the discovery that apoptosis and apoptosis-like cell death evolved due to an evolutionary “arms race” conducted between “prey” protomitochondrion and “predator” primitive eukaryotes. The ancestral protomitochondrial machinery produces and releases toxic mitochondrial proteins. Extant apoptotic factors evolved from these toxins. Our experiments indicate that the mitochondrial machinery is directly involved in adaptation to aerobic conditions. Additionally, our hypothesis is supported by the fact that different apoptotic factors are directly involved in respiration. Full article
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17 pages, 593 KiB  
Review
Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy
by Antoni Domagala, Klaudyna Fidyt, Malgorzata Bobrowicz, Joanna Stachura, Kacper Szczygiel and Malgorzata Firczuk
Int. J. Mol. Sci. 2018, 19(8), 2256; https://doi.org/10.3390/ijms19082256 - 01 Aug 2018
Cited by 55 | Viewed by 7989
Abstract
Lysosomes are conservative organelles with an indispensable role in cellular degradation and the recycling of macromolecules. However, in light of recent findings, it has emerged that the role of lysosomes in cancer cells extends far beyond cellular catabolism and includes a variety of [...] Read more.
Lysosomes are conservative organelles with an indispensable role in cellular degradation and the recycling of macromolecules. However, in light of recent findings, it has emerged that the role of lysosomes in cancer cells extends far beyond cellular catabolism and includes a variety of cellular pathways, such as proliferation, metastatic potential, and drug resistance. It has been well described that malignant transformation leads to alterations in lysosomal structure and function, which, paradoxically, renders cancer cells more sensitive to lysosomal destabilization. Furthermore, lysosomes are implicated in the regulation and execution of cell death in response to diverse stimuli and it has been shown that lysosome-dependent cell death can be utilized to overcome apoptosis and drug resistance. Thus, the purpose of this review is to characterize the role of lysosome in cancer therapy and to describe how these organelles impact treatment resistance. We summarized the characteristics of typical inducers of lysosomal cell death, which exert its function primarily via alterations in the lysosomal compartment. The review also presents other anticancer agents with the predominant mechanism of action different from lysosomal destabilization, the activity of which is influenced by lysosomal signaling, including classical chemotherapeutics, kinase inhibitors, monoclonal antibodies, as well as photodynamic therapy. Full article
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15 pages, 2576 KiB  
Review
Autophagic Regulation of p62 is Critical for Cancer Therapy
by Md. Ariful Islam, Mopa Alina Sooro and Pinghu Zhang
Int. J. Mol. Sci. 2018, 19(5), 1405; https://doi.org/10.3390/ijms19051405 - 08 May 2018
Cited by 161 | Viewed by 15629
Abstract
Sequestosome1 (p62/SQSTM 1) is a multidomain protein that interacts with the autophagy machinery as a key adaptor of target cargo. It interacts with phagophores through the LC3-interacting (LIR) domain and with the ubiquitinated protein aggregates through the ubiquitin-associated domain (UBA) domain. It sequesters [...] Read more.
Sequestosome1 (p62/SQSTM 1) is a multidomain protein that interacts with the autophagy machinery as a key adaptor of target cargo. It interacts with phagophores through the LC3-interacting (LIR) domain and with the ubiquitinated protein aggregates through the ubiquitin-associated domain (UBA) domain. It sequesters the target cargo into inclusion bodies by its PB1 domain. This protein is further the central hub that interacts with several key signaling proteins. Emerging evidence implicates p62 in the induction of multiple cellular oncogenic transformations. Indeed, p62 upregulation and/or reduced degradation have been implicated in tumor formation, cancer promotion as well as in resistance to therapy. It has been established that the process of autophagy regulates the levels of p62. Autophagy-dependent apoptotic activity of p62 is recently being reported. It is evident that p62 plays a critical role in both autophagy and apoptosis. Therefore in this review we discuss the role of p62 in autophagy, apoptosis and cancer through its different domains and outline the importance of modulating cellular levels of p62 in cancer therapeutics. Full article
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19 pages, 1548 KiB  
Review
An Interplay between Senescence, Apoptosis and Autophagy in Glioblastoma Multiforme—Role in Pathogenesis and Therapeutic Perspective
by Elzbieta Pawlowska, Joanna Szczepanska, Magdalena Szatkowska and Janusz Blasiak
Int. J. Mol. Sci. 2018, 19(3), 889; https://doi.org/10.3390/ijms19030889 - 17 Mar 2018
Cited by 67 | Viewed by 11461
Abstract
Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation of their mutual interactions is not completely clear. That regulation seems to be especially important in cancer cells, which [...] Read more.
Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation of their mutual interactions is not completely clear. That regulation seems to be especially important in cancer cells, which have their own program of development and demand more nutrition and energy than normal cells. Glioblastoma multiforme (GBM) belongs to the most aggressive and most difficult to cure cancers, so studies on its pathogenesis and new therapeutic strategies are justified. Using an animal model, it was shown that autophagy is required for GBM development. Temozolomide (TMZ) is the key drug in GBM chemotherapy and it was reported to induce senescence, autophagy and apoptosis in GBM. In some GBM cells, TMZ induces small toxicity despite its significant concentration and GBM cells can be intrinsically resistant to apoptosis. Resveratrol, a natural compound, was shown to potentiate anticancer effect of TMZ in GBM cells through the abrogation G2-arrest and mitotic catastrophe resulting in senescence of GBM cells. Autophagy is the key player in TMZ resistance in GBM. TMZ can induce apoptosis due to selective inhibition of autophagy, in which autophagic vehicles accumulate as their fusion with lysosomes is blocked. Modulation of autophagic action of TMZ with autophagy inhibitors can result in opposite outcomes, depending on the step targeted in autophagic flux. Studies on relationships between senescence, autophagy and apoptosis can open new therapeutic perspectives in GBM. Full article
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