Distinct Transcriptional Programs Mediated by the Ligand-Dependent Full-Length Androgen Receptor and Its Splice Variants in Castration-Resistant Prostate Cancer

Hu, Rong; Lu, Changxue; Mostaghel, Elahe A.; Yegnasubramanian, Srinivasan; Gürel, Meltem Ö.; Tannahill, Carol; Edwards, Joanne; Isaacs, William B.; Nelson, Peter S.; Bluemn, Eric G.; Plymate, Stephen R.; Luo, Jun

doi:10.1158/0008-5472.can-11-3892

Cited by 525 publications

(647 citation statements)

References 20 publications

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“…Therefore, we investigated the influence of exogenous AR-V7 expression on SOCS3 expression in AR-V7-negative LNCaP cells. In concordance with the publication of Hu and colleagues (39) we could confirm that AR-V7 can regulate only a subset of the AR target genes and is unable to downregulate SOCS3 expression. This clearly demonstrates that the full-length androgen receptor is necessary for the androgenic regulation of SOCS3 and that the constitutively active AR-V7 splice variant is unable to influence the STAT3 pathway.…”

Section: Discussionsupporting

confidence: 91%

“…3D). To verify the functionality of the AR-V7 vector, two differentially regulated androgen receptor target genes, PSA and FKBP5, were selected on the basis of published whole-genome expression array data (39). In agreement with that previous study, the AR-V7 splice variant led to a significant increase in FKBP5 expression but was unable to activate PSA mRNA expression.…”

Section: Socs3 Is Expressed In Androgen Receptor-positive Prostate Camentioning

confidence: 56%

“…To further investigate the effect of the androgen receptor on SOCS3 expression in CRPC, we performed experiments in presence of the constitutively active androgen receptor splice variant V7 which frequently contributes to the development of castration resistance (43,44). It is still a matter of debate, whether the AR-V7 variant has a different target gene specificity (39,45). Therefore, we investigated the influence of exogenous AR-V7 expression on SOCS3 expression in AR-V7-negative LNCaP cells.…”

Section: Discussionmentioning

confidence: 99%

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SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Handle

Erb

Luef

et al. 2016

Molecular Cancer Research

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The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment.Implications: SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines.

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Section: Discussionsupporting

confidence: 91%

Section: Socs3 Is Expressed In Androgen Receptor-positive Prostate Camentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

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Erb

Luef

et al. 2016

Molecular Cancer Research

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“…In particular, detection of AR-V7 in circulating tumor cells has been associated with resistance to enzalutamide (Antonarakis et al 2014), which is consistent with the resistance of 22Rv1 cells to this AR antagonist. Here we demonstrate that, unlike therapeutic doses of enzalutamide (Hu et al 2012, Li et al 2013 or AUY922 (Gillis et al 2013, He et al 2013) that increase AR-V7 expression in cell lines, xenografts and ex vivo cultured prostate tumors, treating 22Rv1 cells with low dose combined AUY922 and enzalutamide prevents induction of AR-V7 expression.…”

Section: Discussionmentioning

confidence: 51%

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Centenera¹,

Carter²,

Gillis³

et al. 2015

Endocrine-Related Cancer

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Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspasedependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.

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“…Many of these AR variants (AR-Vs) lack all or part of the transcript encoding the AR-LBD and can be divided into two main classes: those that incorporate a cryptic exon or those arising from exon skipping. Rapid, reversible induction of AR-V expression can be achieved by alternative splicing (Watson et al 2010, Hu et al 2012, Gillis et al 2013, Liu et al 2013, Yu et al 2014b, whereas genomic rearrangements within the AR gene can mediate a fully androgen-independent phenotype through a mechanism of switching AR expression from full-length AR to ARv567es (Nyquist et al 2013). AR-V mRNAs have been identified in prostate cancer cell lines, xenografts, mouse models and, most importantly, patient specimens (Dehm et al 2008, Guo et al 2009, Hu et al 2009, Watson et al 2010, Hornberg et al 2011, McGrath et al 2013, Robinson et al 2015 (Table 2).…”

Section: Ar Splice Variantsmentioning

confidence: 99%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

150

122

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The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

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Distinct Transcriptional Programs Mediated by the Ligand-Dependent Full-Length Androgen Receptor and Its Splice Variants in Castration-Resistant Prostate Cancer

Cited by 525 publications

References 20 publications

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

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