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androgen receptor deficiency in monocytes/ macrophages does not alter adiposity or glucose homeostasis in male mice

Asian Journal of Andrology 2018年第3期20卷 276-283页

作者： Katya B Rubinow Barbara Houston Shari Wang Leela Goodspeed Kayoko Ogimoto Gregory J Morton Christopher McCarty Robert E Braun Stephanie T Page Division of Metabolism Endocrinology and Nutrition Department of Medicine University of Washington School of Medicine Seattle WA 98195 USA Jackson Laboratory Bar Harbor ME 04609 USA

androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. androgen receptor （AR） is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages （M-ARKO） were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition. Wild-type （WT） and M-ARKO mice （12-22 weeks of age, n = 12 per group） were maintained on a regular chow diet for 8 weeks and then switched to a high-fat diet for 8 additional weeks. At baseline and on both the regular chow and high-fat diets, no differences in lean mass or fat mass were observed between groups. Consistent with the absence of differential body weight or adiposity, no differences in food intake （3.0 ± 0.5 g per day for WT mice vs 2.8 ± 0.4 g per day for M-ARKO mice） or total energy expenditure （0.6 ± 0.1 Kcal h-1 for WT mice vs 0.5 ± 0.1 Kcal h-1 for M-ARKO mice） were evident between groups during high-fat feeding. Liver weight was greater in M-ARKO than that in WT mice （1.5 ± 0.1 g vs 1.3 ± 0.0 g, respectively, P = 0.02）. Finally, M-ARKO mice did not exhibit impairments in glucose tolerance or insulin sensitivity relative to WT mice at any study time point. In aggregate, these findings suggest that AR signaling specifically in monocytes/macrophages does not contribute to the regulation of systemic energy balance, adiposity, or insulin sensitivity in male mice.

关键词： androgen receptor knockout mice macrophages male hypogonadism metabolic syndrome

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androgen receptor in bladder cancer:A promising therapeutic target

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Asian Journal of Urology 2020年第3期7卷 284-290页

作者： Abhishek Tripathi Shilpa Gupta Section of Hematology Oncology University of Oklahoma Stephenson Cancer CenterOklahoma CityOKUSA Department of Hematology and Medical Oncology Cleveland Clinic Taussig Cancer InstituteClevelandOHUSA

There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.

关键词： androgen receptor Urothelial carcinoma Bladder cancer Targeted therapy Enzalutamide Cisplatin Testosterone

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androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment

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Asian Journal of Andrology 2017年第5期19卷 538-542页

作者： Karolina Bogefors Yvonne Lundberg Giwercman Jakob Eberhard Olof Stahl Eva Cavallin-Stahl Gabriella Cohn-Cedermark Stefan Arver Aleksander Giwercman Reproductive Medicine Centre Skane University Hospital Malmo Sweden Department of Oncology Skane University Hospital Malmo Sweden Department of Translational Medicine Lund University Malmo Sweden Department of Oncology Skane University Hospital Lund Sweden Radiumhemmet Karolinska HospitalStockholm Sweden Centre of Andrology and Sexual Medicine Karolinska Hospital Stockholm Sweden

Spermatogenesis is an androgen-regulated process that depends on the action of androgen receptor （AR）. Sperm production may be affected in men treated for testicular cancer （TC）, and it is important to identify the factors influencing the timing of spermatogenesis recovery following cancer treatment. It is known that the CAG and GGN repeat numbers affect the activity of the AR; therefore, the aim of this study is to investigate if the CAG and GGN polymorphisms in the AR gene predict recovery of sperm production after TC treatment. TC patients （n = 130） delivered ejaculates at the following time points： postorchiectomy and at 6, 12, 24, 36, and 60 months posttherapy （TO, T6, T12, T24, T36, and T60）. The CAG lengths were categorized into three groups, 〈22 CAG, 22-23 CAG, and 〉23 CAG, and the GGN tracts were also categorized into three groups, 〈23 GGN, 23 GGN, and 〉23 GGN. At T12, men with 22-23 CAG presented with a statistically significantly （P = 0.045） lower sperm concentration than those with other CAG numbers （8.4 × 10^6 ml^-1 vs 16 × 10^6 ml^-1; 95% CI： 1.01-2.65）. This association was robust to omitting adjustment for treatment type and sperm concentration at TO （P= 0.021; 3.7× 10^6 ml^-1 vs 10 × 10^6 ml^-1; 95% CI： 1.13-4.90）. The same trends were observed for total sperm number. The least active AR variant seems to be associated with a more rapid recovery of spermatogenesis. This finding adds to our understanding of the biology of postcancer therapy recovery of fertility in males and has clinical implications.

关键词： androgen receptor CAG and GGN repeat sperm number testicular cancer

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Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer

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Chinese Medical Journal 2024年第3期137卷 338-349页

作者： Feng Xu Kun Xu Lingling Fan Xintong Li Yiqiu Liu Fang Yang Chengjun Zhu Xiaoxiang Guan Department of Oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Oncology Jiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityJiangsu Institute of Cancer ResearchNanjingJiangsu 210009China The Comprehensive Cancer Center of Nanjing Drum Tower Hospital Affiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu 210008China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Personalized Cancer MedicineNanjing Medical UniversityNanjingJiangsu 211166China

Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

关键词： androgen receptor Estrogen receptor beta Triple-negative breast cancer NECTIN4 Oncogenic effects Tumor progression

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Investigation of androgen receptor-dependent alternative splicing has identified a unique subtype of lethal prostate cancer

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Asian Journal of Andrology 2023年第3期25卷 296-308页

作者： Sean Seltzer Paresa N Giannopoulos Tarek A Bismar Mark Trifiro Miltiadis Paliouras Lady Davis Institute for Medical Research Segal Cancer Centre-Jewish General HospitalMontrealQC H3T 1E2Canada Cumming School of Medicine Department of Pathology and Laboratory MedicineUniversity of CalgaryCalgaryAB T2N 1N4Canada Department of Medicine Division of Experimental MedicineMcGill UniversityMontrealQC H4A 3J1Canada Department of Oncology McGill UniversityMontrealQC H4A 3T2Canada

A complete proteomics study characterizing active androgen receptor(AR)complexes in prostate cancer(PCa)cells identified a diversity of protein interactors with tumorigenic annotations,including known RNA splicing factors.Thus,we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression.We selected two AR-interacting RNA splicing factors,Src associated in mitosis of 68 kDa(SAM68)and DEAD(Asp-Glu-Ala-Asp)box helicase 5(DDX5)to examine their associative roles in AR-dependent alternative RNA splicing.To assess the true physiological role of AR in alternative RNA splicing,we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets.As a result,we were able to highlight alternative splicing events of clinical significance.Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression.The physiological significance in PCa was investigated through the application of clinical exon array analysis,where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria.Using a clinical dataset with patients categorized as prostate cancer-specific death(PCSD),these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes.Overall,these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa.Moreover,AR-mediated alternative spicing contributes to aggressive PCa progression,where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.

关键词： alternative RNA splicing androgen receptor exon-gene sets lethal prostate cancer subtype prostate cancer

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androgen receptor signaling and mutations in prostate cancer

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Asian Journal of Andrology 2010年第5期12卷 639-657页

作者： Shahriar Koochekpour Department of Urology and Stanley S. Scott Cancer Center School of Medicine Louisiana State University HealthSciences Center New Orleans LA 70112 USA

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor （AR） expression and function. androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent （AI） progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer （PCa）. Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues.

关键词： androgen receptor germline mutation prostate cancer signaling somatic

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androgen receptor functioned as a suppressor in the prostate cancer cell line PC3 in vitro and in vivo

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Chinese Medical Journal 2009年第22期122卷 2779-2783页

作者： YU Sheng-qiang HAN Bang-min SHAO Yi WU Ji-tao ZHAO Fu-jun LIU Hai-tao SUN Xiao-wen TANG Yue-qing XIA Shu-jie Department of Urology First People's Hospital of Shanghai Jiao Tong University Shanghai 200080 China

Background Prostate cancer is one of the most common urogenital tumors in the world with an increasing incidence in China. androgen deprivation therapy is the major therapeutic option for advanced prostate cancer. However, the role of androgen receptor （AR） in hormone-refractory prostate cancer still remains unclear. This work aimed to investigate the role of AR in an androgen independent prostate cancer cell line by in vitro and in vivo studies. Methods The role of AR in the proliferation and invasion/metastasis ability of PC3-AR9 （a PC3 stable clone expressing human AR driven by natural human AR promoter） were examined with M-IF assay, soft agar assay, chamber invasion assay, wound healing assay, and also with orthotopic xenograft mouse model. Results Restoring androgen receptor in PC3 cells resulted in decreased proliferation and invasion/metastasis ability in MTT, soft agar, chamber invasion and wound healing assay. In the mouse orthotopic xenograft model, PC3-AR9 resulted in smaller primary tumors and metastasis tumors, with a lower proliferation rate and higher apoptosis rate. Conclusion The AR might function as a tumor suppressor in PC3 cells both in vitro and in vivo.

关键词： androgen receptor prostate cancer androgen independent orthotopic xenograft

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androgen receptor expression in clinically localized prostate cancer： immunohistochemistry study and literature review

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Asian Journal of Andrology 2008年第6期10卷 855-863页

作者： Yi-Qing Qiu Ivo Leuschner Peter Martin Braun Department of Urology the Second Affliated Hospital of Zhejiang University Hangzhou 310009 China Department of Urology and Pediatric Urology Department of Pathology Universitgitsklinikum Schleswig-Holstein Campus Kiel Kiel 24105 Germany

Aim： To evaluate androgen receptor （AR） expression in clinically localized prostate cancer （PCa）. Methods： Specimens were studied from 232 patients who underwent radical prostatectomy for clinically localized prostatic adenocarcinoma without neoadjuvant hormonal therapy or chemotherapy at our institution between November 2001 and June 2005. Immunohistochemical study was performed using an anti-human AR monoclonal antibody AR441. The mean AR density in the hot spots of different histological areas within the same sections were compared and the correlation of malignant epithelial AR density with clinicopathological parameters such as Gleason score, tumor, nodes and metastases （TNM） stage and pre-treatment prostate-specific antigen （PSA） value was assessed. Results： AR immunoreactivity was almost exclusively nuclear and was observed in tumor cells, non-neoplastic glandular epithelial cells and a proportion of peritumoral and interglandular stromal cells. Mean percentage of AR-positive epithelial cells was significantly higher in cancer tissues than that in normal prostate tissues （mean e SD, 90.0% ± 9.3% vs. 85.3% ±9.7%, P 〈 0.001）. The histological score yielded similar results. The percentage ofAR immunoreactive prostatic cancer nuclei and histological score were not correlated with existing parameters such as Gleason score, tumor, nodes and metastases stage and pre-treatment PSA value in this surgically treated cohort. Conclusion： The results of the present study suggest that there may be limited clinical use for determining AR expression （if evaluated in hot spots） in men with localized PCa.

关键词： androgen receptor prostate cancer immunohistochemistry

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Rauwolfia vomitoria extract suppresses benign prostatic hyperplasia by reducing expression of androgen receptor and 5a-reductase in a rat model

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Journal of Integrative Medicine 2021年第3期19卷 258-264页

作者： Tian Fang Ze-sheng Xue Jia-xuan Li Jia-kuan Liu Di Wu Mei-qian Li Yu-ting Song Shi-feng Yun Jun Yan Department of Comparative Medicine Jinling HospitalNanjing University School of MedicineNanjing 210002Jiangsu ProvinceChina Center for Veterinary Drug Research and Evaluation College of Veterinary MedicineNanjing Agricultural UniversityNanjing 210095Jiangsu ProvinceChina Model Animal Research Center of Nanjing University Nanjing 210061Jiangsu ProvinceChina Department of Laboratory Animal Science Fudan UniversityShanghai 200032China Ministry of Education Key Laboratory of Model Animals for Disease Study Model Animal Research Center of Nanjing UniversityNanjing 210061Jiangsu ProvinceChina Department of Information Jinling HospitalNanjing University School of MedicineNanjing 210002Jiangsu ProvinceChina

Objective:Herbal medicine is an important therapeutic option for benign prostatic hyperplasia(BPH),a common disease in older men that can seriously affect their quality of life.Currently,it is crucial to develop agents with strong efficacy and few side effects.Herein we investigated the effects of the extract of Rauwolfia vomitoria,a shrub grown in West Africa,on BPH.Methods:Rats with testosterone-induced BPH were treated with R.vomitoria.Prostates were histologically analyzed by Hematoxylin and eosin staining.Proliferation index and the expression levels of androgen receptor and its associated proteins were quantified through immunohistochemistry and immunoblotting.androgen receptor target genes were examined by quantitative real-time polymerase chain reaction.The sperm count and body weight of rats were also measured.Results:The oral administration of R.vomitoria extract significantly reduced the prostate weight and prostate weight index in BPH rats,supported by the decreased thickness of the prostate epithelial layer and increased lumen size.Similar effects were observed in the BPH rats treated with the reference drug,finasteride.R.vomitoria extract significantly reduced the testosterone-induced proliferation markers,including proliferating cell nuclear antigen and cyclin D1,in the prostate glands of BPH rats;it also reduced levels of androgen receptor,its associated protein steroid 5 a-reductase 1 and its downstream target genes(FK506-binding protein 5 and matrix metalloproteinase 2).Notably,compared with the finasteride group,R.vomitoria extract did not significantly reduce sperm count.Conclusion:R.vomitoria suppresses testosterone-induced BPH development.Due to its milder side effects,R.vomitoria could be a promising therapeutic agent for BPH.

关键词： Benign prostatic hyperplasia Rat model Herbal extract androgen receptor Rauwolfia vomitoria

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Discovery of Novel androgen receptor Ligands by Structure-based Virtual Screening and Bioassays

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Genomics, Proteomics & Bioinformatics 2018年第6期16卷 416-427页

作者： Wenfang Zhou Mojie Duan Weitao Fu Jinping Pang Qin Tang Huiyong Sun Lei Xu Shan Chang Dan Li Tingjun Hou College of Pharmaceutical Sciences Zhejiang University State Key Laboratory of Computer Aided Design and Computer Graphics (CAD&GC) Zhejiang University State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics National Center for Magnetic Resonance in WuhanWuhan Institute of Physics and MathematicsChinese Academy of Sciences Institute of Bioinformatics and Medical Engineering School of Electrical and Information EngineeringJiangsu University of Technology

androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.

关键词： androgen receptor AR ligand Virtual screening AR agonist AR antagonist

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