Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target

Shiota, Masaki; Yokomizo, Akira; Naito, Seiji

doi:10.1530/jme-11-0018

Cited by 99 publications

(93 citation statements)

References 175 publications

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“…Many studies have shown that the progression of CRPC is associated with increased AR expression (Gregory et al 1998, Zegarra-Moro et al 2002, Chen et al 2004, Scher & Sawyers 2005, which can be attributed to gene amplification, transcriptional up-regulation, translational up-regulation, and decreased degradation. As we summarized previously (Shiota et al 2011b (Mizokami et al 1994), and Foxo3a (Yang et al 2005), regulate AR expression. In addition, it has recently been shown that the SREBP-1 transcription factor regulates AR expression (Huang et al 2010), is overexpressed during progression to castration resistance (Ettinger et al 2004), regulates lipogenesis, and induces oxidative stress via NADPH oxidase 5 (Nox5) expression that can be reversed by the Nox inhibitor diphenyliodonium (DPI).…”

Section: Ar Overexpressionmentioning

confidence: 57%

“…AR overexpression is thought to be one of the major causes of CRPC (Shiota et al 2011b). Many studies have shown that the progression of CRPC is associated with increased AR expression (Gregory et al 1998, Zegarra-Moro et al 2002, Chen et al 2004, Scher & Sawyers 2005, which can be attributed to gene amplification, transcriptional up-regulation, translational up-regulation, and decreased degradation.…”

Section: Ar Overexpressionmentioning

confidence: 99%

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Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

Shiota

Yokomizo

Naito

2012

Endocrine-Related Cancer

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Oxidative stress caused by an increase in reactive oxygen species levels or a decrease in cellular antioxidant capacity can evoke the modulation of various cellular events including androgen receptor (AR) signaling via direct or indirect interactions. In this review, we summarize the mechanisms of AR activation by oxidative stress including: i) AR overexpression; ii) AR activation by AR co-regulators or intracellular signal transduction pathways; iii) generation of AR mutations or splice variants; and iv) de novo androgen synthesis. AR signaling augmented by oxidative stress appears to contribute to pro-survival and anti-apoptotic effects in prostate cancer cells in response to androgen deprivation therapy. In addition, AR signaling suppresses anti-survival and pro-apoptotic effects in prostate cancer cells in response to various cytotoxic and tumorsuppressive interventions including taxanes and radiation through the modulation of bIII-tubulin and ataxia telangiectasia-mutated kinase expression respectively. Taken together, AR signaling appears to render prostate cancer cells refractory to various therapeutic interventions including castration, taxanes, and radiation, indicating that AR signaling is a comprehensive resistant factor and crucial target for prostate cancer treatment.

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Section: Ar Overexpressionmentioning

confidence: 57%

Section: Ar Overexpressionmentioning

confidence: 99%

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

Shiota

Yokomizo

Naito

2012

Endocrine-Related Cancer

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“…Briefly, a mixture of 2 Â 10 6 LNCaP or VCaP cells were suspended in 0.0375 mL RPMI þ 10% FBS and 0.0625 mL Matrigel/animal and were injected subcutaneously. Once the tumor size reached 200 to 300 mm 3 , the animals were castrated or sham operated, randomized, DHT pellets were implanted subcutaneously or not supplemented, and treated as indicated in the figures. Tumor volume and body weight were measured.…”

Section: Tumor Xenograft Experimentsmentioning

confidence: 99%

“…Overexpression of AR and coactivators drives the growth and metastasis of CRPC even in response to low levels of androgens (3)(4)(5). Despite having castrate levels of serum testosterone, tumor samples obtained from men with CRPC have only a 60% reduction in intratumoral dihydrotestosterone (DHT).…”

Section: Introductionmentioning

confidence: 99%

Steroidogenic Enzyme AKR1C3 Is a Novel Androgen Receptor-Selective Coactivator that Promotes Prostate Cancer Growth

Yepuru

Kulkarni

et al. 2013

Clinical Cancer Research

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Purpose: Castration-resistant prostate cancer (CRPC) may occur by several mechanisms including the upregulation of androgen receptor (AR), coactivators, and steroidogenic enzymes, including aldo keto reductase 1C3 (AKR1C3). AKR1C3 converts weaker 17-keto androgenic precursors to more potent 17-hydroxy androgens and is consistently the major upregulated gene in CRPC. The studies in the manuscript were undertaken to examine the role of AKR1C3 in AR function and CRPC.Experimental Design: LNCaP cells stably transfected with AKR1C3 and VCaP cells endogenously expressing AKR1C3 were used to understand the effect of AKR1C3 on prostate cancer cell and tumor growth in nude mice. Chromatin immunoprecipitation, confocal microscopy, and co-immunoprecipitation studies were used to understand the recruitment of AKR1C3, intracellular localization of AKR1C3 and its interaction with AR in cells, tumor xenograft, and in Gleason sum 7 CRPC tissues. Cells were transiently transfected for AR transactivation. Novel small-molecule AKR1C3-selective inhibitors were synthesized and characterized in androgen-dependent prostate cancer and CRPC models.Results: We identified unique AR-selective coactivator-and prostate cancer growth-promoting roles for AKR1C3. AKR1C3 overexpression promotes the growth of both androgen-dependent prostate cancer and CRPC xenografts, with concomitant reactivation of androgen signaling. AKR1C3 interacted with AR in prostate cancer cells, xenografts, and in human CRPC samples and was recruited to the promoter of an androgen-responsive gene. The coactivator and growth-promoting functions of AKR1C3 were inhibited by an AKR1C3-selective competitive inhibitor.Conclusions: AKR1C3 is a novel AR-selective enzymatic coactivator and may represent the first of more than 200 known nuclear hormone receptor coactivators that can be pharmacologically targeted.

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“…Despite high initial response rates, remissions following ADT are temporary due to the emergence of castration-resistant prostate cancer (CRPC), where AR reactivation occurs and tumors grow in the presence of low levels of androgens. AR activation remains a central mechanism driving CRPC progression (4), involving variable combinations of AR gene amplification, increased AR sensitivity, promiscuous AR-binding mutants, altered expression of coregulators, ligand-independent activation by oncogenic signaling pathways, and increases in androgen biosynthesis (5)(6)(7)(8). These mechanisms likely work in concert to drive CRPC; hence, targeting the AR remains a critical component of novel CRPC therapies (9,10).…”

Section: Introductionmentioning

confidence: 99%

A Novel Antiandrogen, Compound 30, Suppresses Castration-Resistant and MDV3100-Resistant Prostate Cancer Growth In Vitro and In Vivo

Kuruma¹,

Matsumoto²,

Shiota³

et al. 2013

Molecular Cancer Therapeutics

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105

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Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inhibits androgen receptor (AR) activity in LNCaP cells, C4-2 cells, as well as MDV3100-resistant cell lines. Compared with MDV3100, Compound 30 treatment induces greater reduction in AR, prostate-specific antigen (PSA), and AR transcriptional activity, and prevents AR nuclear translocation in AR-sensitive LNCaP cells. Compound 30 has antiproliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100-resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100-resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors. Mol Cancer Ther; 12(5); 567–76. ©2013 AACR.

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Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target

Cited by 99 publications

References 175 publications

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

Steroidogenic Enzyme AKR1C3 Is a Novel Androgen Receptor-Selective Coactivator that Promotes Prostate Cancer Growth

A Novel Antiandrogen, Compound 30, Suppresses Castration-Resistant and MDV3100-Resistant Prostate Cancer Growth In Vitro and In Vivo

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