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Life Science Alliance Sep 2023The Hippo signalling pathway is a master regulator of cell growth, proliferation, and cancer. The transcriptional coregulators of the Hippo pathway, YAP and TAZ, are...
The Hippo signalling pathway is a master regulator of cell growth, proliferation, and cancer. The transcriptional coregulators of the Hippo pathway, YAP and TAZ, are central in various cancers. However, how YAP and TAZ get activated in most types of cancers is not well understood. Here, we show that androgens activate YAP/TAZ via the androgen receptor (AR) in prostate cancer (PCa), and that this activation is differential. AR regulates YAP translation while inducing transcription of the TAZ encoding gene, Furthermore, we show that AR-mediated YAP/TAZ activation is regulated by the RhoA GTPases transcriptional mediator, serum response factor (SRF). Importantly, in prostate cancer patients, expression positively correlates with and the YAP/TAZ target genes and We demonstrate that YAP/TAZ are not essential for sustaining AR activity, however, targeting YAP/TAZ or SRF sensitize PCa cells to AR inhibition in anchorage-independent growth conditions. Our findings dissect the cellular roles of YAP, TAZ, and SRF in prostate cancer cells. Our data emphasize the interplay between these transcriptional regulators and their roles in prostate tumorigenesis and highlight how these insights might be exploited therapeutically.
Topics: Humans; Male; Androgens; Carcinogenesis; Prostate; Prostatic Neoplasms; Receptors, Androgen; Transcriptional Coactivator with PDZ-Binding Motif Proteins
PubMed: 37385752
DOI: 10.26508/lsa.202201620 -
Scientific Reports Aug 2023Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor...
Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with β integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly β integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Syndecan-1; Androgen Antagonists; Androgens; Integrin beta3; Neoplastic Processes
PubMed: 37596305
DOI: 10.1038/s41598-023-40347-7 -
Biology of Sex Differences Sep 2023Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated...
BACKGROUND
Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC and explored a promising combination drug regimen to enhance the efficacy of immunotherapy.
METHODS
Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen-androgen receptor axis in sex differences was explored in vivo and in vitro experiments.
RESULTS
Our analysis of scRNA-seq data from 220,156 cells, as well as MxIF and FCM assays, revealed that CD8 T-cells infiltrated highly in the TME of male RCC, but were mostly in an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8 T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8 T-cells and enhance the efficacy of immunotherapy of RCC in vivo.
CONCLUSIONS
Our study delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen-androgen receptor axis plays an important role in immunosuppression in male RCC. Our findings suggest that androgen receptor inhibitors in combination with immunotherapy may be a promising treatment option for male RCC patients.
Topics: Female; Humans; Male; Carcinoma, Renal Cell; CD8-Positive T-Lymphocytes; Receptors, Androgen; Sex Characteristics; Androgens; Single-Cell Analysis; Kidney Neoplasms; Tumor Microenvironment
PubMed: 37715192
DOI: 10.1186/s13293-023-00540-9 -
Nature Communications Oct 2023Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to...
Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to greater exposure to ultraviolet radiation or indicate a role for androgenic pathways in the pathogenesis of skin cancers. We dissected this relationship via Mendelian randomization (MR) analyses, using genetic data from recent male-only meta-analyses of cutaneous melanoma (12,232 cases; 20,566 controls) and keratinocyte cancers (KCs) (up to 17,512 cases; >100,000 controls), followed by stratified MR analysis by body-sites. We found strong associations between MPB and the risk of KC, but not with androgens, and multivariable models revealed that this relationship was heavily confounded by MPB single nucleotide polymorphisms involved in pigmentation pathways. Site-stratified MR analyses revealed strong associations between MPB with head and neck squamous cell carcinoma and melanoma, suggesting that sun exposure on the scalp, rather than androgens, is the main driver. Men with less hair covering likely explains, at least in part, the higher incidence of melanoma in men residing in countries with high ambient UV.
Topics: Humans; Male; Skin Neoplasms; Testosterone; Melanoma; Ultraviolet Rays; Alopecia; Androgens
PubMed: 37789011
DOI: 10.1038/s41467-023-41231-8 -
International Journal of Molecular... Jul 2023Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in women. Previously, we suggested that human mesenchymal stem cells (MSCs) can reverse...
Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in women. Previously, we suggested that human mesenchymal stem cells (MSCs) can reverse the PCOS condition by secreting factors. Here, we evaluated the therapeutic capability of MSC-derived extracellular vesicles (EVs), also known as exosomes, in both in vitro and in vivo PCOS models. Exosomes were used to treat androgen-producing H293R cells and injected in a mouse model through intraovarian and intravenous injection into a letrozole (LTZ)-induced PCOS mouse model. We assessed the effects of the exosomes on androgen-producing cells or the PCOS mouse model by analyzing steroidogenic gene expression (quantitative real-time polymerase chain reaction (qRT-PCR)), body weight change, serum hormone levels, and fertility by pup delivery. Our data show the therapeutic effect of MSC-derived EVs for reversing PCOS conditions, including fertility issues. Interestingly, intravenous injection was more effective for serum glucose regulation, and an intraovarian injection was more effective for ovary restoration. Our study suggests that MSC-derived exosomes can be promising biopharmaceutics for treating PCOS conditions as a novel therapeutic option. Despite the fact that we need more validation in human patients, we may evaluate this novel treatment option for PCOS with the following clinical trials.
Topics: Animals; Mice; Humans; Female; Polycystic Ovary Syndrome; Androgens; Extracellular Vesicles; Mesenchymal Stem Cells
PubMed: 37446328
DOI: 10.3390/ijms241311151 -
Cell Reports Oct 2023Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly...
Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.
Topics: Humans; Male; Androgens; Cell Line, Tumor; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-myc; Receptors, Androgen; Signal Transduction
PubMed: 37815914
DOI: 10.1016/j.celrep.2023.113221 -
Frontiers in Endocrinology 2023Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer,... (Meta-Analysis)
Meta-Analysis
AIMS
Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer, combined with spironolactone, an antiandrogen medication, may exert complementary effects on PCOS. We therefore performed a meta-analysis of trials in which metformin combined with spironolactone was applied to treat PCOS to evaluate the efficacy and safety of the combination therapy.
METHODS
We retrieved the PubMed, Embase, Scopus, Cochrane Library, CNKI, CBM, Wangfang, and VIP databases for literatures published from their inception to December 16, 2022 on the effects of metformin combined with spironolactone in the treatment of PCOS. Inclusion criteria according to P.I.C.O.S criteria were: PCOS patients, metformin combined with spironolactone interventions, metformin alone control group, and randomized controlled trials with the following outcome data: body mass index (BMI), hirsutism score, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), fasting blood glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and side effects including nausea, vomiting, diarrhea and drug withdrawal.
RESULTS
Our results revealed that metformin combined with spironolactone significantly reduced BMI and TT, but that it exerted no significant effects on hirsutism score, or on FSH or LH concentrations. Combined treatment also resulted in a significant diminution in FBG and insulin resistance using the HOMA-IR when the interventional time was greater than 6 months. In addition, the combination did not have a higher occurrence of adverse reactions than metformin alone.
CONCLUSION
Compared with metformin alone, metformin combined with spironolactone therapy may be more effective in reducing BMI and serum androgen levels, but the combination showed no significant effect on the hirsutism score or gonadotropin hormone levels, and was not associated with an elevation in side-effects. Moreover, when the treatment course was greater than 6 months, combination therapy reduced FBG and improved insulin resistance more effectively than metformin alone. However, more research is needed to determine the most effective course of treatment.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022355515.
Topics: Female; Humans; Hirsutism; Insulin Resistance; Polycystic Ovary Syndrome; Spironolactone; Drug-Related Side Effects and Adverse Reactions; Follicle Stimulating Hormone, Human; Luteinizing Hormone
PubMed: 37635987
DOI: 10.3389/fendo.2023.1223768 -
Proceedings of the National Academy of... Jul 2023Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with...
Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that (), a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, an AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted. Due to continued interest in proxalutamide, which is in phase 3 trials, we examined its ability to impact SARS-CoV-2 infection and downstream inflammatory responses. Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of and , the SARS-CoV-2 receptor. However, proxalutamide led to degradation of AR protein, which was not observed with enzalutamide. Proxalutamide inhibited SARS-CoV-2 infection with an IC value of 97 nM, compared to 281 nM for enzalutamide. Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir. Proxalutamide protected against cell death in response to tumor necrosis factor alpha and interferon gamma, and overall survival of mice was increased with proxalutamide treatment prior to cytokine exposure. Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.
Topics: Male; Humans; Animals; Mice; COVID-19; SARS-CoV-2; Androgens; Androgen Antagonists; Pandemics; Peptidyl-Dipeptidase A; Prostatic Neoplasms; Interferon-gamma
PubMed: 37459541
DOI: 10.1073/pnas.2221809120 -
Current Opinion in Endocrinology,... Dec 2023Androgens (also known as anabolic-androgenic steroids; AAS) are increasingly being abused worldwide to enhance body physique or athletic performance. Qualitative studies... (Review)
Review
PURPOSE OF REVIEW
Androgens (also known as anabolic-androgenic steroids; AAS) are increasingly being abused worldwide to enhance body physique or athletic performance. Qualitative studies including interviews provide a wider understanding of androgen abuse and focus specific support needs to this group. This narrative review summarizes recent studies (2021-2023) using interviews with individuals abusing androgens.
RECENT FINDINGS
Motivations for androgen abuse in men include desires to achieve certain physicality, enhance self-confidence and improve libido. The risks of androgen abuse are justified to achieve these outcomes and men may use other illicit substances as postcycle-therapy to lessen the risks. Some adverse effects may be more pronounced with certain substances. The therapeutic relationship with healthcare professionals is often described negatively by androgen abusers due to stigma and a perceived lack of knowledge. Both healthcare professionals and androgen abusers agree that development of guidelines are needed. Androgen abuse in women is rare however body dissatisfaction and desires for improve appearance and strength are motivators.
SUMMARY
Recent qualitative studies have helped further our understanding of men and women who abuse androgens, however the small number of recently published studies confirms there is still a paucity of evidence in the literature. Further research is needed to develop specific harm minimization strategies in those abusing androgens.
Topics: Male; Humans; Female; Androgens; Anabolic Agents; Anabolic Androgenic Steroids; Athletic Performance; Drug-Related Side Effects and Adverse Reactions
PubMed: 37646503
DOI: 10.1097/MED.0000000000000834 -
The American Journal of Pathology Mar 2024Endocrine therapy for prostate cancer is based on the use of drugs that diminish androgen concentration and androgen receptor (AR) signaling inhibitors and is limited by... (Review)
Review
Endocrine therapy for prostate cancer is based on the use of drugs that diminish androgen concentration and androgen receptor (AR) signaling inhibitors and is limited by the functional consequences of AR point mutations and increased expression of constitutively active receptors. Many coactivators (>280) interact with different AR regions. Most studies have determined the expression of coactivators and their effects in the presence of increasing concentrations of androgen or the antiandrogen enzalutamide. The p160 group of coactivators (SRC-1, SRC-2, and SRC-3) is highly expressed in prostate cancer and contributes to ligand-dependent activation of the receptor in models that represent therapy-sensitive and therapy-resistant cell lines. The transcriptional coactivators p300 and CREB-binding protein (CBP) are implicated in the regulation of a large number of cellular events, such as proliferation, apoptosis, migration, and invasion. AR coactivators also may predict biochemical and clinical recurrence. The AR coactivator expression, which is enhanced in enzalutamide resistance, includes growth regulating estrogen receptor binding 1 (GREB1) and GATA-binding protein 2 (GATA2). Several coactivators also activate AR-unrelated signaling pathways, such as those of insulin-like growth factors, which inhibit apoptosis in cancer cells. They are expressed in multiple models of resistance to therapy and can be targeted by various inhibitors in vitro and in vivo. The role of the glucocorticoid receptor in endocrine therapy-resistant prostate cancer has been documented previously. Specific coactivators may interact with the glucocorticoid receptor, thus contributing to therapy failure.
Topics: Male; Humans; Androgens; Receptors, Androgen; Receptors, Glucocorticoid; Histone Acetyltransferases; Prostatic Neoplasms; Cell Line, Tumor; Benzamides; Nitriles; Phenylthiohydantoin
PubMed: 38104650
DOI: 10.1016/j.ajpath.2023.12.003