Search Results (110)

The Anti-Müllerian hormone (AMH) is widely recognized for promoting Müllerian duct regression in higher vertebrates and regulating key reproductive functions like steroidogenesis, folliculogenesis, and Leydig cell development. In teleost fish, which lack Müllerian ducts, Amh primarily influences male reproductive functions, including sex determination, testis differentiation, and germ cell proliferation. In adult fish, Amh supports gonad development and spermatogenesis, but its role in teleost gonadal physiology remains largely underexplored. This study reveals a novel steroidogenic function in the European sea bass (Dicentrarchus labrax) using in vitro testis culture, in vivo plasmid injection, and cell-based transactivation assays. The Amh-induced significant increase in androgen levels was also confirmed in Japanese medaka (Oryzias latipes) treated with recombinant sea bass Amh. Beyond activating the canonical Smad pathway, Amh also triggered the cAMP/PKA signalling pathway via its cognate type II receptor, Amhr2. Inhibitors of these pathways independently and synergistically counteracted Amh-induced CRE-Luc activity, indicating pathway crosstalk. Moreover, inhibition of the cAMP pathway suppressed Amh-induced androgen production in testis cultures, emphasizing the crucial role of protein kinase A in mediating Amh steroidogenic action. These findings uncover a novel steroidogenic function of Amh in teleosts and highlight its broader role in male reproductive physiology. Full article

Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism (HH) characterized by gonadotropin-releasing hormone (GnRH) deficiency and anosmia due to defective neuronal migration. While traditionally considered irreversible, cases of spontaneous improvement of HH have been reported, suggesting residual GnRH neuronal function in some individuals. We present a case of a 29-year-old man with KS who exhibited spontaneous recovery of endogenous testosterone production following the cessation of long-term androgen therapy without the use of alternative hormonal agents. After ceasing testosterone therapy for several months, the patient’s total testosterone levels normalized (407–424 ng/dL), accompanied by increased secondary sexual characteristics, stable gonadotropin levels, and normal testicular volume. Persistent anosmia was noted, suggesting that restoration of reproductive endocrine function can occur independently of olfactory recovery. Genetic testing identified heterozygous mutations in PCSK1 and HS6ST1, genes implicated in GnRH regulation and KS pathogenesis. This case highlights the potential role of genetic variation in spontaneous HH improvement and underscores the need for individualized management strategies, including periodic reassessment of gonadal function and fertility potential. Further research is needed to elucidate the mechanisms driving spontaneous HH improvement, identify predictive biomarkers of reversibility, and explore therapeutic strategies that may promote endogenous GnRH activity in select patients with KS. Full article

Introduction: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, X-linked, progressive neuromuscular disease caused by abnormal CAG trinucleotide expansion in the androgen receptor gene. Patients with SBMA report difficulty with falls on self-reported activities of daily living scales. To our knowledge, no study has examined the relationship between falls and common clinical measures of strength, balance, mobility, and disease biomarkers. We performed a cross-sectional analysis of an SBMA cohort. Objectives: The objectives of this study are as follows: (1) compare demographics, clinical measures, and biomarkers between patients who did and did not fall; (2) determine which measures best discriminate fallers from non-fallers; and (3) identify cutoff scores to detect patients with a higher fall risk. Design: Cross-sectional analysis was used. Outcome Measures: Disease biomarkers included blood serum creatinine, and clinical measures included the Timed Up and Go (TUG), the Adult Myopathy Assessment Tool (AMAT), and posturography, including the Modified Clinical Test of Sensory Interaction on Balance and the Motor Control Test. The Maximal Voluntary Isometric Contractions (MVICs) of four lower extremity muscles were captured via fixed-frame dynamometry. Results: We identified three clinical measures that help detect fall risk in people with SBMA. A post hoc receiver operating characteristic curve analysis helped identify cut scores for each test. Impairments of mobility (TUG > 8 s), muscle endurance (AMAT endurance subscale < 14), and muscle strength (ankle plantar flexion MVIC < 45% of predicted) were different between fallers and non-fallers, via independent t-tests. Conclusions: These three clinical tests can help detect fall risk that may help clinicians implement gait aid use or other fall prevention strategies before catastrophic falls occur. Full article

Prostate cancer (PCa) is a major global health concern, particularly in advanced stages where chemotherapy resistance and androgen-independent tumor growth reduce survival rates to below 30%. Toll-like receptor 3 (TLR3), regulated by tumor suppressor p53, is a promising therapeutic target due to its role in tumor cell apoptosis. However, chronic exposure to inorganic arsenic (iAs), a known carcinogen, has been linked to PCa progression and reduced TLR3 expression and activation by polyinosinic/polycytidylic acid (Poly(I/C)), a synthetic ligand used in PCa immunotherapy. Here, we demonstrate that chronic sodium arsenite (NaAsO) exposure increases p53 transcript and protein levels in immortalized prostate epithelial cells. Despite this, key p53 target genes, including TLR3, CDKN1A, and BAX, were significantly downregulated, indicating a transcriptionally inactive p53. Chromatin immunoprecipitation (ChIP) confirmed diminished p53 binding to TLR3 and CDKN1A promoters, while sequencing ruled out TP53 mutations. A bioinformatic analysis revealed elevated TP53 but reduced TLR3 and CDKN1A in prostate adenocarcinoma, suggesting that iAs-induced oxidative stress disrupts p53 function. These findings reveal a novel mechanism by which iAs promotes PCa progression through impaired p53 activity, highlighting the need to explore post-translational and epigenetic factors affecting p53. Restoring p53 transcriptional activity may offer a therapeutic strategy for PCa patients exposed to NaAsO. Full article

The liver is the most lethal metastatic site in castration-resistant prostate cancer (CRPC). Overexpression of MET protein has been reported in CRPC, and MET is an important driver gene in androgen-independent CRPC cells. Mouse CRPC cell line CRTC2 was established by subcutaneous injection of hormone-sensitive PC cells (TRAMP-C2) in castrated nude mice. CRCT2/luc2 cells were injected into the spleen of castrated nude mice, and liver metastasis was confirmed at 2 weeks post-injection. We administered MET inhibitor (MET-I) and HGF activator inhibitor (HGFA-I) to this liver metastasis model and assessed the therapeutic effect. After intrasplenic injection, CRTC2 showed a higher incidence of liver metastasis whereas no metastasis was observed in TRAMP-C2. Microarray analysis revealed increased expression of HGF, MET, and HPN, HGFAC (encoding HGF activating proteases) in liver metastasis. Proliferation of CRCT2 was significantly inhibited by co-administration of MET-I and HGFA-I by in vitro analysis with HGF-enriched condition. In an analysis of the mouse model, the combination-therapy group showed the strongest reduction for liver metastasis. Immunohistochemical staining also revealed the strongest decrease in phosphorylation of MET in the combination-therapy group. Co-culture with HGF-expressed mouse fibroblasts showed attenuation of the inhibitory effect of MET-I; however, additional HGFA-I overcame the resistance. We established an androgen-independent CRPC cell line, CRTC2, and liver metastasis model in mice. Significant effect was confirmed by combined treatment of MET-I and HGFA-I by in vitro and in vivo analysis. The results suggested the importance of combined treatment with both MET- and HGF-targeting agents in the treatment of HGF-enriched conditions including liver metastasis. Full article

Purpose: To identify molecular changes during PCa invasion of adipose space using Spatial Transcriptomic Profiling of PCa cells. Methods: This study was performed on paired intraprostatic and extraprostatic samples obtained from radical prostatectomy with pT3a pathological stages. Results: Differential gene expression revealed upregulation of heat shock protein genes: DNAJB1, HSPA8, HSP90AA1, HSPA1B, HSPA1A in PCa PanCK+ cells from the adipose periprostatic space. Extraprostatic extension was significantly associated with overexpression of genes involved in metastatic spread (EGR1, OR51E2, SPON2), of aggressiveness ERG negative signature of enhancers of androgen receptor (HOXB13, FOXA1), and of PSMA (FOLH1). They were associated with loss at 6q, 10q, 16q, and gain at 8q24 locus. Conclusions: PCa invasion of adipose EPE induces adaptative process related to heat shock proteins; PCa cells in EPE also present transcriptomics signatures for ERG independent aggressiveness, androgen receptor co-activation, and specific CNV changes. Full article

Primary osteoporosis is closely linked to hormone deficiency, which disrupts the balance of bone remodeling. It affects postmenopausal women but also significantly impacts older men. Estrogen can promote the production of osteoprotegerin, a decoy receptor for RANKL, thereby preventing RANKL from activating osteoclasts. Furthermore, estrogen promotes osteoblast survival and function via activation of the Wnt signaling pathway. Likewise, androgens play a critical role in bone metabolism, primarily through their conversion to estrogen in men. Estrogen deficiency accelerates bone resorption through a rise in pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and RANKL, which promote osteoclastogenesis. In the classic genomic pathway, estrogen binds to estrogen receptors in the cytoplasm, forming a complex that migrates to the nucleus and binds to estrogen response elements on DNA, regulating gene transcription. Androgens can be defined as high-affinity ligands for the androgen receptor; their combination can serve as a ligand-inducible transcription factor. Hormone replacement therapy has shown promise but comes with associated risks and side effects. In contrast, the non-genomic pathway involves rapid signaling cascades initiated at the cell membrane, influencing cellular functions without directly altering gene expression. Therefore, the ligand-independent actions and rapid signaling pathways of estrogen and androgen receptors can be harnessed to develop new drugs that provide bone protection without the side effects of traditional hormone therapies. To manage primary osteoporosis, other pharmacological treatments (bisphosphonates, teriparatide, RANKL inhibitors, sclerostin inhibitors, SERMs, and calcitonin salmon) can ameliorate osteoporosis and improve BMD via actions on different pathways. Non-pharmacological treatments include nutritional support and exercise, as well as the dietary intake of antioxidants and natural products. The current study reviews the processes of bone remodeling, hormone actions, hormone receptor status, and therapeutic targets of primary osteoporosis. However, many detailed cellular and molecular mechanisms underlying primary osteoporosis seem complicated and unexplored and warrant further investigation. Full article

17α-Methyltestosterone (MT) is a widely used androgen for all-male fish production in aquaculture. However, the molecular mechanism underlying MT-induced masculinization remains unclear. In this study, we aim to identify the key gene responsible for MT-induced masculinization using the Nile tilapia (Oreochromis niloticus) amhy, dmrt1, and gsdf mutants, which exhibit male-to-female sex reversal. Nile tilapia fry from these three mutant lines were treated with 50 μg/g MT from 5 to 30 days after hatching (dah). The results showed that amhy and gsdf mutants, but not dmrt1 mutants, were masculinized by the MT treatment. Gonadal transcriptome analysis revealed that genes involved in steroidogenesis and germ cell development in MT-treated dmrt1 mutants exhibited a similar expression pattern to that of the wild type (WT) XX. In addition, the dmrt1 mutants cannot be masculinized by co-treatment with MT and the aromatase inhibitor fadrozole. The MT treatment completely blocked early steroidogenic enzyme (Star2, Cyp17a2, and Cyp19a1a) expression independent of amhy, gsdf, and dmrt1. A luciferase analysis showed that MT directly suppressed basal and Sf-1-activated cyp19a1a promoter activity through ara and arb in cultured HEK293 cells. Furthermore, MT treatment inhibited germ cell proliferation in amhy and gsdf mutants but not in dmrt1 mutants. Consistently, dmrt1 expression was induced in MT-treated WT XX, -amhy, and -gsdf mutants. Taken together, these results suggest that dmrt1 is indispensable for MT-induced masculinization in Nile tilapia and that MT functions by inhibiting early steroid synthesis and activating dmrt1 to promote testis development. Full article

For many years, it has been speculated that elevated testosterone levels may be critically involved in the genesis and proliferation of prostate cancer. Methods: The effect of testosterone on the metabolic activity of hormone-independent [PC-3] and hormone-dependent [LNCAP] cancer cells was investigated in vitro. Additionally, the impact of testosterone nanoemulsion [nanocare^®] on cell viability was accessed by flow cytometry. Results: Despite the dependency of the normal prostate and of most prostatic cancers upon androgens, the obtained results indicate that, contrary to prevailing opinion, the supplementation of testosterone with higher doses in nanoemulsion was able to lower the metabolic activity and viability of prostate cancer cells. Conclusions: We conclude that the growth of hormone-independent and hormone-dependent prostate cancer cells was reduced by the exposure of a nanoemulsion of bioidentical testostosterone in vitro. To the best of our knowledge, this is the first time that the potential effect of a testosterone nanoemulsion on the metabolic activity of prostate cancer cells has been shown. Such tests suggest that the growth of hormone-independent and hormone-dependent prostate cancer cells was reduced by the administration of bioidentical testostosterone, and this might be an interesting strategy for prostate cancer treatment in diagnosed patients. Full article

Metastatic castration-resistant prostate cancer (mCRPC) remains a deadly disease due to a lack of efficacious treatments. The reprogramming of cancer metabolism toward elevated glycolysis is a hallmark of mCRPC. Our goal is to identify therapeutics specifically associated with high glycolysis. Here, we established a computational framework to identify new pharmacological agents for mCRPC with heightened glycolysis activity under a tumor microenvironment, followed by in vitro validation. First, using our established computational tool, OncoPredict, we imputed the likelihood of drug responses to approximately 1900 agents in each mCRPC tumor from two large clinical patient cohorts. We selected drugs with predicted sensitivity highly correlated with glycolysis scores. In total, 77 drugs predicted to be more sensitive in high glycolysis mCRPC tumors were identified. These drugs represent diverse mechanisms of action. Three of the candidates, ivermectin, CNF2024, and P276-00, were selected for subsequent vitro validation based on the highest measured drug responses associated with glycolysis/OXPHOS in pan-cancer cell lines. By decreasing the input glucose level in culture media to mimic the mCRPC tumor microenvironments, we induced a high-glycolysis condition in PC3 cells and validated the projected higher sensitivity of all three drugs under this condition (p < 0.0001 for all drugs). For biomarker discovery, ivermectin and P276-00 were predicted to be more sensitive to mCRPC tumors with low androgen receptor activities and high glycolysis activities (AR(low)Gly(high)). In addition, we integrated a protein–protein interaction network and topological methods to identify biomarkers for these drug candidates. EEF1B2 and CCNA2 were identified as key biomarkers for ivermectin and CNF2024, respectively, through multiple independent biomarker nomination pipelines. In conclusion, this study offers new efficacious therapeutics beyond traditional androgen-deprivation therapies by precisely targeting mCRPC with high glycolysis. Full article

Prostate cancer (PCa) is characterised by androgen dependency. Unfortunately, under anti-androgen treatment pressure, castration-resistant prostate cancer (CRPC) emerges, characterised by heterogeneous cell populations that, over time, lead to the development of different androgen-dependent or -independent phenotypes. Despite important advances in therapeutic strategies, CRPC remains incurable. Context-specific essential genes represent valuable candidates for targeted anti-cancer therapies. Through the investigation of gene and protein annotations and the integration of published transcriptomic data, we identified two consensus lists to stratify PCa patients’ risk and discriminate CRPC phenotypes based on androgen receptor activity. ROC and Kaplan–Meier survival analyses were used for gene set validation in independent datasets. We further evaluated these genes for their association with cancer dependency. The deregulated expression of the PCa-related genes was associated with overall and disease-specific survival, metastasis and/or high recurrence risk, while the CRPC-related genes clearly discriminated between adeno and neuroendocrine phenotypes. Some of the genes showed context-specific essentiality. We further identified candidate drugs through a computational repositioning approach for targeting these genes and treating lethal variants of PCa. This work provides a proof-of-concept for the use of an integrative approach to identify candidate biomarkers involved in PCa progression and CRPC pathogenesis within the goal of precision medicine. Full article

Prostate cancer (PCa) often becomes drug-treatment-resistant, posing a significant challenge to effective management. Although initial treatment with androgen deprivation therapy can control advanced PCa, subsequent resistance mechanisms allow tumor cells to continue growing, necessitating alternative approaches. This study delves into the specific metabolic dependencies of different PCa subtypes and explores the potential synergistic effects of combining androgen receptor (AR) inhibition (ARN with mitochondrial complex I inhibition (IACS)). We examined the metabolic behaviors of normal prostate epithelial cells (PNT1A), androgen-sensitive cells (LNCaP and C4-2), and androgen-independent cells (PC-3) when treated with ARN, IACS, or a combination. The results uncovered distinct mitochondrial activities across PCa subtypes, with androgen-dependent cells exhibiting heightened oxidative phosphorylation (OXPHOS). The combination of ARN and IACS significantly curbed cell proliferation in multiple PCa cell lines. Cellular bioenergetics analysis revealed that IACS reduced OXPHOS, while ARN hindered glycolysis in certain PCa cells. Additionally, galactose supplementation disrupted compensatory glycolytic mechanisms induced by metabolic reprogramming. Notably, glucose-deprived conditions heightened the sensitivity of PCa cells to mitochondrial inhibition, especially in the resistant PC-3 cells. Overall, this study illuminates the intricate interplay between AR signaling, metabolic adaptations, and treatment resistance in PCa. The findings offer valuable insights into subtype-specific metabolic profiles and propose a promising strategy to target PCa cells by exploiting their metabolic vulnerabilities. Full article

Prostate cancer (PCa) is the leading cancer in men globally. The association between PCa and long non-coding RNAs (lncRNAs) has been reported. Aberrantly expressed lncRNAs have been documented in each of the cancer “hallmarks”. Androgen signaling plays an important role in PCa progression. This study aimed to profile the aberrantly expressed lncRNAs in androgen-dependent (LNCaP) PCa compared to androgen-independent (PC-3) PCa cells. This was achieved by using a 384-well plate of PCa lncRNA gene panel. Differential expression of ±2 up or downregulation was determined using the CFX Maestro software v2.1. LncSEA and DIANA-miRPath were used to identify the enriched pathways. Telomerase RNA component (TERC) lncRNA was illustrated to participate in various tumourigenic classes by in silico bioinformatics analysis and was thus selected for validation using RT-qPCR. Further bioinformatics analysis revealed the involvement of differentially expressed lncRNAs in oncogenic pathways. Some lncRNAs undergo hypermethylation, others are encapsulated by exosomes, while others interact with several microRNAs (miRNAs), favouring tumourigenic pathways. Notably, TERC lncRNA was shown to interact with tumour-suppressor miRNAs hsa-miR-4429 and hsa-miR-320b. This interaction in turn activates TGF-β-signaling and ECM-receptor interaction pathways, favouring the progression of PCa. Understanding lncRNAs as competitive endogenous RNA molecules and their interactions with miRNAs may aid in the identification of novel prognostic PCa biomarkers and therapeutic targets. Full article

Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained unclear. Although aging and androgen have been reported as definitive risk factors for BPH, recent studies have focused on the involvement of androgen-independent factors. Androgen-independent factors include ischemia, oxidative stress, metabolic syndrome, infection, autoimmune reactions, and inflammation, with inflammation in BPH tissues playing a central role in the BPH proliferative process. Inflammation in BPH tissues by various factors finally leads to tissue remodeling and stromal proliferation through the wound healing process of the prostate. To elucidate the proliferative mechanism of BPH, a study using whole-genome gene expression analysis in a stromal-dominant BPH rat model was performed and showed that immune response-related pathways and complement classical pathways are activated. Furthermore, expression analysis using this BPH rat model showed that the autoimmune reaction triggered complement pathway activation in the proliferative process of BPH. BPH is a multifactorial disease, and understanding the role of androgen-independent factors including immune responses contributes to elucidating the pathogenesis of BPH. Androgen-independent factors may lead to new therapeutic targets for BPH, and further development of this research is expected. Full article

The methyltransferase KMT5A has been proposed as an oncogene in prostate cancer and therefore represents a putative therapeutic target. To confirm this hypothesis, we have performed a microarray study on a prostate cancer cell line model of androgen independence following KMT5A knockdown in the presence of the transcriptionally active androgen receptor (AR) to understand which genes and cellular processes are regulated by KMT5A in the presence of an active AR. We observed that 301 genes were down-regulated whilst 408 were up-regulated when KMT5A expression was reduced. KEGG pathway and gene ontology analysis revealed that apoptosis and DNA damage signalling were up-regulated in response to KMT5A knockdown whilst protein folding and RNA splicing were down-regulated. Under these conditions, the top non-AR regulated gene was found to be CDC20, a key regulator of the spindle assembly checkpoint with an oncogenic role in several cancer types. Further investigation revealed that KMT5A regulates CDC20 in a methyltransferase-dependent manner to modulate histone H4K20 methylation within its promoter region and indirectly via the p53 signalling pathway. A positive correlation between KMT5A and CDC20 expression was also observed in clinical prostate cancer samples, further supporting this association. Therefore, we conclude that KMT5A is a valid therapeutic target for the treatment of prostate cancer and CDC20 could potentially be utilised as a biomarker for effective therapeutic targeting. Full article