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Chawnshang Chang - One of the best experts on this subject based on the ideXlab platform.
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adt with Antiandrogens in prostate cancer induces adverse effect of increasing resistance neuroendocrine differentiation and tumor metastasis
Cancer Letters, 2018Co-Authors: Yuanjie Niu, Chawnshang Chang, Shuyuan Yeh, Changcheng Guo, Simeng Wen, Jing Tian, Jie Luo, Keliang Wang, Hao TianAbstract:Prostate cancer (PCa) is the most common cancer and the 2nd leading cause of cancer-related deaths among men in the United States. Androgen-deprivation-therapy (ADT) with Antiandrogens to target the androgens/androgen receptor (AR) signals remains the standard therapy for advanced PCa. However, most of the PCa patients who received ADT with Antiandrogens, including the recently developed Enzalutamide (Enz) that might extend PCa patients survival an extra 4.8 months, will still develop the castration (or antiandrogen) resistance. Mechanism dissection studies suggest these antiandrogen resistances may involve the induction of AR splicing variants and/or AR mutants. Further preclinical in vitro/in vivo studies suggest ADT-Antiandrogens may also enhance the neuroendocrine differentiation (NED) and PCa cell invasion, and these unwanted side-effects may function through various mechanisms including altering the infiltrating inflammatory cells within the prostate tumor microenvironment. This review summarizes these unwanted ADT-induced side-effects and discusses multiple approaches to overcome these side-effects to better suppress the PCa at the castration resistant stage.
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reducing the agonist activity of Antiandrogens by a dominant negative androgen receptor coregulator ara70 in prostate cancer cells
Journal of Biological Chemistry, 2003Co-Authors: Mujib Rahman, Hiroshi Miyamoto, Shuyuan Yeh, Saleh Altuwaijri, Hiroshi Takatera, Chawnshang ChangAbstract:Abstract Although the progression of prostate cancer initially is dependent on androgens, tumor progression to an androgen-independent growth eventually occurs in most of patients treated with androgen ablation and/or antiandrogen therapy. After the initial response, Antiandrogens lose their efficacy and eventually act as agonists to promote androgen receptor (AR)-mediated growth of prostate cancer cells. An aberrant regulation of AR activity, presumably by AR coregulators, may contribute to this acquired agonist activity of Antiandrogens. Using an in vitro mutagenesis and a double-negative selection in yeast two-hybrid screening, we have identified a dominant-negative AR coregulator ARA70 (dARA70N), which can inhibit AR transcriptional activity by inactivating the normal function of ARA70 in the LNCaP cells. Whereas ARA70 in oligomeric form interacts with AR and enhances its transcriptional activity, dARA70N lacks AR interaction and might retain the ability to form a non-functional heteromer with ARA70 and interrupt AR transcriptional activity without a change in AR protein itself. The addition of dARA70N reduces the agonist activity and rescues the normal function of Antiandrogens in prostate cancer cells. RNA-interference-mediated silencing of ARA70 gene further confirms these observations. Taken together, these findings indicate that ARA70 may contribute to the acquired agonist activity of Antiandrogens and plays an important role in making prostate cancer cells resistant to androgen ablation and/or antiandrogen therapy. ARA70 may, thus, be a critical target for developing therapeutic agents against AR-mediated progression of prostate cancer.
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inactivation of androgen receptor coregulator ara55 inhibits androgen receptor activity and agonist effect of Antiandrogens in prostate cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Mujib Rahman, Hiroshi Miyamoto, Henry A Lardy, Chawnshang ChangAbstract:Antiandrogens given to antagonize androgen receptor (AR) activity gradually lose their efficacy as antagonists and eventually function as agonists to promote (instead of block) AR-mediated growth of prostate cancer cells. The mechanisms of how Antiandrogens acquire this agonist activity during hormonal therapy are largely unknown. Here, we report that expression of a dominant-negative AR-associated protein 55 (dARA55) coregulator, inhibits AR transcriptional activity and reduces the agonist activity of Antiandrogens. Inducibly expressed dARA55 inhibits prostate-specific antigen and cell growth in prostate cancer cells. Further dissection of the molecular mechanism shows dARA55 can selectively suppress endogenous AR-associated protein 55 (ARA55) enhanced AR transactivation by means of interruption of dimerization between ARA55 and ARA55. These results were confirmed by using RNA interference-mediated silencing of the ARA55 gene. These results therefore provide evidence that AR function could be suppressed without mutation or change in AR itself. Taken together, these findings not only demonstrate the important roles of the ARA55 coregulator in the AR-mediated growth of prostate cancer, they also may provide a critical target for developing therapeutic agents for the antiandrogen therapy that almost always fails in the treatment of hormone-refractory prostate cancer.
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3β acetoxyandrost 1 5 diene 17 ethylene ketal functions as a potent antiandrogen with marginal agonist activity
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Hiroshi Miyamoto, Padma Marwah, Ashok Marwah, Henry A Lardy, Chawnshang ChangAbstract:The majority of available Antiandrogens have been reported to possess agonist activity to induce prostate-specific antigen, which might result in antiandrogen withdrawal syndrome. Here we report the identification of 3β-acetoxyandrost-1,5-diene-17-ethylene ketal (ADEK) from dehydroepiandrosterone metabolites and derivatives as a potent antiandrogen. We found ADEK could interrupt androgen binding to the androgen receptor (AR) and suppress androgen-induced transactivations of WT AR and a mutant AR in prostate cancer cells. ADEK inhibited prostate-specific antigen expression as well as growth in LNCaP prostate cancer cells stimulated by androgen. Importantly, ADEK had only marginal agonist effects, as compared with commonly used Antiandrogens such as hydroxyflutamide and bicalutamide, leading to a lower possibility of inducing withdrawal response. Moreover, ADEK could block an adrenal androgen androstenediol-induced AR transactivation that hydroxyflutamide and bicalutamide failed to block. These unique antiandrogenic activities make ADEK a potential therapeutic compound that might be able to inhibit AR-mediated prostate cancer progression. Further in vivo studies might facilitate the development of a better antiandrogen for the treatment of prostate cancer.
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Functional analysis of androgen receptor N-terminal and ligand binding domain interacting coregulators in prostate cancer
Journal of the Formosan Medical Association = Taiwan yi zhi, 2000Co-Authors: Shuyuan Yeh, Cheng Lung Hsu, Yuh-ling Chen, Erik R. Sampson, Dong Kun Lee, Eungseok Kim, Hong-chiang Chang, Saleh Altuwaijri, Chawnshang ChangAbstract:Several new androgen receptor (AR) coregulators, including ARA70, ARA55, ARA54, ARA160 and ARA24, associated with the N-terminal or the ligand-binding domain (LBD) of AR, have been identified by our group. We first identified the AR-LBD coregulators ARA70, ARA55, and ARA54. Our previous reports suggest that ARA70 can enhance the androgenic activity of 17 beta-estradiol (E2) and Antiandrogens toward AR. It is of interest to compare and determine if the specificity of sex hormones and Antiandrogens can be modulated by different coregulators. Our results indicate that, ARA70 is the best coregulator for increasing the androgenic activity of E2. Only ARA70 and ARA55 were able to significantly increase the androgenic activity of hydroxyflutamide, the active metabolite of a widely-used antiandrogen for the treatment of prostate cancer. Furthermore, our results suggest that among the LBD coregulators, ARA70 has a relatively high specificity for AR in the human prostate cancer cell line DU145. Together, our data suggest that the androgenic activity of some sex hormones and Antiandrogens can be modulated by selective AR coactivators. In addition to the AR-LBD associated proteins, ARA24 and ARA160 have been identified as AR coregulators, interacting with the AR N-terminal instead of the LBD. Functional analysis revealed that the AR N-terminal coregulator ARA160 could cooperate with the AR LBD-associated coregulator ARA70. Our data indicate that ARA24 could also interact with AR, and that this binding is decreased by an expanding poly-glutamine (Q) length within AR. The length of the poly-Q stretch in the AR N-terminal domain is inversely correlated with the transcriptional activity of AR. Our data suggest that optimal AR transactivation may require interaction of AR with AR coregulators. The identification of factors or peptides that can interrupt androgen-mediated AR-ARA interactions may be useful in the development of better Antiandrogens for treating androgen-related diseases, such as prostate cancer.
Peter T. Nieh - One of the best experts on this subject based on the ideXlab platform.
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Withdrawal phenomenon with the antiandrogen casodex.
The Journal of Urology, 1995Co-Authors: Peter T. NiehAbstract:Total androgen blockade with castration and Antiandrogens has become the primary therapy in metastatic prostate carcinoma. Several reports have been published on the flutamide withdrawal syndrome with a favorable response in patients with progression of disease after lengthy remission while taking combined hormone therapy. The experience with withdrawal of the experimental nonsteroidal antiandrogen casodext in 3 patients is reported. All patients received casodex monotherapy initially, then luteinizing hormone-releasing hormone analogues were added on progression of disease (bone scan and prostate specific antigen [PSAI) and eventually casodex was withdrawn on further progression of disease (PSA and bone scan). Two patients had declines in PSA levels of 42% and 75% sustained for 3 to 6 months, and 1 patient had a stable condition for 2 months. These responses were similar to those of withdrawal of flutamide, which were limited to patients who had received combination therapy at the onset of treatment. Thus, the observations in this report would suggest that the initial and sustained exposure to an antiandrogen is the more important factor in the withdrawal phenomenon rather than the low androgen environment alone that occurs with initial luteinizing hormone-releasing hormone analogue monotherapy, orchi&my or combination luteinizing hormone-releasing hormone anaTotal androgen blockade with combined surgical or medical castration and Antiandrogens has become the mainstay of therapy for patients with stage D2 carcinoma of the prostate. Several recent reports have been published of favorable clinical and prostate specific antigen (PSA) responses to the withdrawal of the antiandrogen flutamide in patients with progression of disease &r lengthy remission while taking combined hormone therapy for metastatic carcinoma of the prostate. This paradoxical response may contribute to some of those reported with various second line treatments. Experience with withdrawal of the experimental nonsteroidal antiandrogen casodex in 3 patients is reported. MATERIALS AND METHODS All patients were enrolled into the casodex monotherapy trial for metastatic stage D2 carcinoma of the prostate, which compared results with the antiandrogen casodex with castration (either orchiectomy or medical castration using a goserelin acetate implant). These 3 patients were randomized to receive 50 mg. casodex daily and demonstrated excellent responses for the first year. At the time of progression of clinical disease with evidence of deterioration seen on bone scans and a considerable increase in PSA, luteinizing hormone-releasing hormone agonist therapy was added with improvement in symptoms, PSA and bone scan results. Eventually, when progression of disease recurred casodex was discontinued while the patients continued to take the luteinizing hormone-releasing hormone analogue.
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Withdrawal phenomenon with the antiandrogen casodex. Commentaries
The Journal of Urology, 1995Co-Authors: Peter T. Nieh, E. D. Crawford, Howard I. Scher, William Kevin KellyAbstract:Total androgen blockade with castration and Antiandrogens has become the primary therapy in metastatic prostate carcinoma. Several reports have been published on the flutamide withdrawal syndrome with a favorable response in patients with progression of disease after lengthy remission while taking combined hormone therapy. The experience with withdrawal of the experimental nonsteroidal antiandrogen casodex in 3 patients is reported. All patients received casodex monotherapy initially, then luteinizing hormone-releasing hormone analogues were added on progression of disease (bone scan and prostate specific antigen [PSA]) and eventually casodex† was withdrawn on further progression of disease (PSA and bone scan). Two patients had declines in PSA levels of 42% and 75% sustained for 3 to 6 months, and 1 patient had a stable condition for 2 months. These responses were similar to those of withdrawal of flutamide, which were limited to patients who had received combination therapy at the onset of treatment. Thus, the observations in this report would suggest that the initial and sustained exposure to an antihydrogen is the more important factor in the withdrawal phenomenon rather than the low androgen environment alone that occurs with initial luteinizing hormone-releasing hormone analogue monotherapy, orchiectomy or combination luteinizing hormone-releasing hormone analogue and antiandrogen
Joerg J Meerpohl - One of the best experts on this subject based on the ideXlab platform.
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non steroidal antiandrogen monotherapy compared with luteinizing hormone releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer a cochrane systematic review
BJUI, 2015Co-Authors: Frank Kunath, Henrik R Grobe, Gerta Rucker, Edith Motschall, Gerd Antes, Philipp Dahm, Bernd Wullich, Joerg J MeerpohlAbstract:To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced hormone-sensitive stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomized controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced hormone-sensitive stages of prostate cancer. Two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias as well as quality of evidence according to the GRADE working group guidelines. We used Review Manager 5.2 for data synthesis and the fixed-effect model as primary analysis (when heterogeneity was low with I(2) < 50%); we used a random-effects model when confronted with substantial or considerable heterogeneity (when I(2) ≥50%). A total of 11 studies involving 3060 randomly assigned participants were included in the present review. Use of non-steroidal Antiandrogens resulted in lower overall survival times (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.48, six studies, 2712 participants) and greater clinical progression (1 year: risk ratio [RR] 1.25, 95% CI 1.08-1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08-1.45, six studies, 2373 participants; 2 years: RR 1.14, 95% CI 1.04-1.25, three studies, 1336 participants), as well as treatment failure (1 year: RR 1.19, 95% CI 1.02-1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05-1.52, five studies, 1845 participants; 2 years: RR 1.14, 95% CI 1.05-1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Use of non-steroidal Antiandrogens increased the risk for treatment discontinuation as a result of adverse events (RR 1.82, 95% CI 1.13-2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79- 35.67, eight studies, 2670 participants) and gynaecomastia (RR 8.43, 95% CI 3.19-22.28, nine studies, 2774 participants) The risk of other adverse events, such as hot flushes (RR 0.23, 95% CI 0.19-0.27, nine studies, 2774 participants) was decreased when non-steroidal Antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flushes was rated as moderate according to GRADE. The effects of non-steroidal Antiandrogens on cancer-specific survival and biochemical progression remained unclear. Non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation resulting from adverse events. Evidence quality was rated as moderate according to GRADE; therefore, further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy.
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non steroidal antiandrogen monotherapy compared with luteinising hormone releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer
Cochrane Database of Systematic Reviews, 2014Co-Authors: Frank Kunath, Henrik R Grobe, Gerta Rucker, Edith Motschall, Gerd Antes, Philipp Dahm, Bernd Wullich, Joerg J MeerpohlAbstract:Background Non-steroidal Antiandrogens and castration are the main therapy options for advanced stages of prostate cancer. However, debate regarding the value of these treatment options continues. Objectives To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinising hormone–releasing hormone agonists or surgical castration monotherapy for treating advanced stages of prostate cancer. Search methods We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. Selection criteria We included randomised controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced stages of prostate cancer. Data collection and analysis One review author screened all titles and abstracts; only citations that were clearly irrelevant were excluded at this stage. Then, two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, assessed trial quality and extracted data. We contacted the study authors to request additional information. We used Review Manager 5 for data synthesis and used the fixed-effect model for heterogeneity less than 50%; we used the random-effects model for substantial or considerable heterogeneity. Main results Eleven studies involving 3060 randomly assigned participants were included in this review. The quality of evidence is hampered by risk of bias. Use of non-steroidal Antiandrogens decreased overall survival (hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.05 to 1.48, six studies, 2712 participants) and increased clinical progression (one year: risk ratio (RR) 1.25, 95% CI 1.08 to 1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08 to 1.45, six studies, 2373 participants; two years: RR 1.14, 95% CI 1.04 to 1.25, three studies, 1336 participants), as well as treatment failure (one year: RR 1.19, 95% CI 1.02 to 1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05 to 1.52, five studies, 1845 participants; two years: RR 1.14, 95% CI 1.05 to 1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Predefined subgroup analyses showed that use of non-steroidal Antiandrogens, compared with castration, was less favourable for overall survival, clinical progression (at one year, 70 weeks, two years) and treatment failure (at one year, 70 weeks, two years) in men with metastatic disease. Use of non-steroidal Antiandrogens also increased the risk for treatment discontinuation due to adverse events (RR 1.82, 95% CI 1.13 to 2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79 to 35.67, eight studies, 2670 participants), gynaecomastia (RR 8.43, 95% CI 3.19 to 22.28, nine studies, 2774 participants) and asthenia (RR 1.77, 95% CI 1.36 to 2.31, five studies, 2073 participants). The risk of other adverse events, such as hot flashes (RR 0.23, 95% CI 0.19 to 0.27, nine studies, 2774 participants), haemorrhage (RR 0.07, 95% CI 0.01 to 0.54, two studies, 546 participants), nocturia (RR 0.38, 95% CI 0.20 to 0.69, one study, 480 participants), fatigue (RR 0.52, 95% CI 0.31 to 0.88, one study, 51 participants), loss of sexual interest (RR 0.50, 95% CI 0.30 to 0.83, one study, 51 participants) and urinary frequency (RR 0.22, 95% CI 0.11 to 0.47, one study, 480 participants) was decreased when non-steroidal Antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flashes was rated as moderate according to GRADE. The effects of non-steroidal Antiandrogens on cancer-specific survival and biochemical progression remained unclear. Authors' conclusions Currently available evidence suggests that use of non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation due to adverse events. Evidence quality was rated as moderate according to GRADE. Further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy. However, we believe that research is likely not necessary on non-steroidal antiandrogen monotherapy for men with metastatic prostate cancer. Only high-quality, randomised controlled trials with long-term follow-up should be conducted. If further research is planned to investigate biochemical progression, studies with standardised follow-up schedules using measurements of prostate-specific antigen based on current guidelines should be conducted.
Guoyan Geng - One of the best experts on this subject based on the ideXlab platform.
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synthesis and in vitro characterization of ionone based chalcones as novel Antiandrogens effective against multiple clinically relevant androgen receptor mutants
Investigational New Drugs, 2010Co-Authors: Jinming Zhou, Guoyan GengAbstract:A crucial event in prostate cancer progression is the transition from a hormone-sensitive to a lethal castration-refractory disease state. The antagonist-to-agonist conversion due to mutation in AR is a critical problem with the current clinically used Antiandrogens. We aim to identify novel Antiandrogens that remain as a pure antagonist even in the mutated ARs. By synthesizing a series of ionone-based chalcones, we have identified a novel chalcone (17) that is a pan-antagonist of the wild type and the clinically relevant T877A, W741C and H874Y mutated ARs in luciferase reporter assays in PC-3 cells. Further, chalcone 17 demonstrates sub-micromolar to low micromolar antiproliferative activity in LNCaP, MDA-PCa-2b, 22Rv1 and C4-2B prostate cancer cells, all of which express mutated ARs and confer resistance to the current clinically used Antiandrogens. The results suggest that chalcone 17 could be a good candidate for further pre-clinical development as a novel antiandrogen for advanced prostate cancer.
Heather L. Montie - One of the best experts on this subject based on the ideXlab platform.
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inhibition of stat5a b enhances proteasomal degradation of androgen receptor liganded by Antiandrogens in prostate cancer
Molecular Cancer Therapeutics, 2015Co-Authors: David T. Hoang, Lei Gu, Zhiyong Liao, Feng Shen, Pooja Talati, Mateusz Koptyra, Elyse Ellsworth, Shilpa Gupta, Heather L. MontieAbstract:Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with Antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, Bicalutamide, Flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the Prostate Specific Antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using Antiandrogens may be substantially improved by targeting of Stat5a/b.
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Inhibition of Stat5a/b enhances proteasomal degradation of androgen receptor liganded by Antiandrogens in prostate cancer
Molecular Cancer Therapeutics, 2014Co-Authors: David T. Hoang, Lei Gu, Zhiyong Liao, Feng Shen, Pooja Talati, Mateusz Koptyra, Elyse Ellsworth, Shilpa Gupta, Heather L. MontieAbstract:Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with Antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, Bicalutamide, Flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the Prostate Specific Antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using Antiandrogens may be substantially improved by targeting of Stat5a/b.
