Androgen receptor decoy molecules block the growth of prostate cancer

Quayle, Steven N.; Mawji, Nasrin R.; Wang, Jun; Sadar, Marianne D.

doi:10.1073/pnas.0606718104

Cited by 79 publications

(83 citation statements)

References 22 publications

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“…These observations suggest that the AR NTD could play a key role in mediating aberrant AR activity in ADI prostate cancer cells. This hypothesis is supported by the finding that a decoy peptide representing the entire AR NTD can inhibit AR activity and prostate cancer tumor growth, and thereby delay emergence of an ADI phenotype in a xenograft-based model of prostate cancer progression (11).…”

Section: Introductionsupporting

confidence: 60%

Selective Role of an NH2-Terminal WxxLF Motif for Aberrant Androgen Receptor Activation in Androgen Depletion–Independent Prostate Cancer Cells

et al. 2007

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Systemic prostate cancer therapy requires androgen ablation, which inhibits the production or action of androgens. Prostate cancer ultimately relapses during androgen ablation, and an androgen depletion-independent (ADI) phenotype emerges. Aberrant androgen receptor (AR) activation underlies therapy resistance at this stage of the disease, and mounting evidence implicates the large and highly disordered AR NH 2 -terminal domain (NTD) as a key mediator of this activity. In this study, we investigated the role of the NTD transactivation unit 5 (TAU5) domain in mediating AR transcriptional activity in cell-based models of prostate cancer progression. AR replacement and Gal4-based promoter tethering experiments revealed that AR TAU5 had a dichotomous function, inhibiting ligand-dependent AR activity in androgen-dependent prostate cancer cells, while enhancing ligand-independent AR activity in ADI prostate cancer cells. Molecular dissection of TAU5 showed that a WxxLF motif was fully responsible for its ligandindependent activity. Mechanistically, WxxLF did not rely on an interaction with the AR ligand-binding domain to mediate ligand-independent AR activity. Rather, WxxLF functioned as an autonomous transactivation domain. These data show that ligand-dependent and ligand-independent AR activation rely on fundamentally distinct mechanisms, and define WxxLF as the major transactivation motif within the AR TAU5 domain.

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Section: Introductionsupporting

confidence: 60%

Selective Role of an NH2-Terminal WxxLF Motif for Aberrant Androgen Receptor Activation in Androgen Depletion–Independent Prostate Cancer Cells

et al. 2007

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“…For example, the Nutlin compounds were developed to block MDM2 interaction with p53, consequently stabilizing the p53 tumor suppressor and inducing cell cycle arrest and apoptosis (49). Furthermore, expression of the NH 2 -terminal region of AR has been shown to block the growth of prostate cancer (50). Additionally, targeting BAF57 could potentially be useful in combination with the commonly used therapy of AR antagonists (e.g., bicalutamide), as examination of BAF57 and SWI/ SNF function on antagonist treatment revealed no functional requirement for the complex in antagonist-mediated repression (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity

Link¹,

Balasubramaniam²,

Sharma³

et al. 2008

Cancer Research

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The androgen receptor (AR) is critical for disseminated prostate cancer proliferation and survival. AR activity is targeted either through prevention of ligand synthesis or through the use of antagonists that bind the COOH-terminal ligandbinding domain. Although initially effective, treatment fails due to restored AR activity in the presence of therapeutics. Thus, new means must be developed to target AR activity. The SWI/SNF chromatin remodeling complex is critical for AR transcriptional activity, and the BAF57 SWI/SNF subunit facilitates direct interaction with the receptor. Although selected SWI/SNF subunit expression is reduced in prostate cancer, we show that BAF57 is retained in human disease and is elevated in a subset of tumors. Functional analyses showed that BAF57 contributes uniquely to androgen-mediated stimulation of transcription without compromising the effectiveness of AR antagonists. Subsequent studies revealed that BAF57 is recruited to the AR DNA-binding domain/hinge region, which occurs concomitant with receptor activation. These data provided the basis for a novel inhibitor derived from BAF57 [BAF57 inhibitory peptide (BIPep)], which blocked AR residence on chromatin and resultant AR-dependent gene activation. Importantly, BIPep expression was sufficient to inhibit androgen-dependent prostate cancer cell proliferation in AR-positive cells. In summary, these data identify blockade of AR-BAF57 interaction as a novel means to target agonistinduced AR function in prostate cancer, and provide the first evidence that abrogation of SWI/SNF function can be developed as a point of therapeutic intervention in prostate cancer. [Cancer Res 2008;68(12):4551-8]

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“…Patients succumb to metastatic CRPC usually within 2 years of onset. In vivo proof-of-principle demonstration of therapeutic response by targeting the AR NTD in CRPC was first shown with decoy proteins (20), and then with EPI-001, a small molecule that inhibits transactivation of AR NTD (21).…”

Section: Introductionmentioning

confidence: 99%

An androgen receptor N-terminal domain antagonist for treating prostate cancer

et al. 2013

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Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.

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Androgen receptor decoy molecules block the growth of prostate cancer

Cited by 79 publications

References 22 publications

Selective Role of an NH2-Terminal WxxLF Motif for Aberrant Androgen Receptor Activation in Androgen Depletion–Independent Prostate Cancer Cells

Selective Role of an NH2-Terminal WxxLF Motif for Aberrant Androgen Receptor Activation in Androgen Depletion–Independent Prostate Cancer Cells

Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity

An androgen receptor N-terminal domain antagonist for treating prostate cancer

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