Abstract
Upregulation of constitutively-active androgen receptor splice variants (AR-Vs) has been implicated in AR-driven tumor progression in castration-resistant prostate cancer. To date, functional studies of AR-Vs have been focused mainly on their ability to regulate gene expression independent of the full-length AR (AR-FL). Here, we showed that AR-V7 and ARv567es, two major AR-Vs, both facilitated AR-FL nuclear localization in the absence of androgen and mitigated the ability of the antiandrogen enzalutamide to inhibit AR-FL nuclear trafficking. AR-V bound to the promoter of its specific target without AR-FL, but co-occupied the promoter of canonical AR target with AR-FL in a mutually-dependent manner. AR-V expression attenuated both androgen and enzalutamide modulation of AR-FL activity/cell growth, and mitigated the in vivo antitumor efficacy of enzalutamide. Furthermore, ARv567es levels were upregulated in xenograft tumors that had acquired enzalutamide resistance. Collectively, this study highlights a dual function of AR-Vs in mediating castration resistance. In addition to trans-activating target genes independent of AR-FL, AR-Vs can serve as a "rheostat" to control the degree of response of AR-FL to androgen-directed therapy via activating AR-FL in an androgen-independent manner. The findings shed new insights into the mechanisms of AR-V-mediated castration resistance and have significant therapeutic implications.
Highlights
Androgen deprivation therapy, which disrupts androgen receptor (AR) signaling through androgen ablation or AR antagonists, is the first-line treatment for disseminated prostate cancer
The ability of AR splice variants (AR-Vs) to contribute to castration resistance has been attributed largely to their AR-FL-independent constitutive activity in regulating gene expression
We showed that AR-V7 and ARv567es, two major AR-Vs, facilitate AR-FL nuclear localization in the absence of androgen and mitigate the ability of the antiandrogen enzalutamide to inhibit androgen-induced AR-FL nuclear localization
Summary
Androgen deprivation therapy, which disrupts androgen receptor (AR) signaling through androgen ablation or AR antagonists, is the first-line treatment for disseminated prostate cancer While this regimen is effective initially, progression to the presently incurable and lethal stage, termed castration-resistant prostate www.impactjournals.com/oncotarget cancer (CRPC), invariably occurs [1,2]. CRPC tissues were shown to exhibit persistent levels of androgens despite androgen deprivation [1,2] These led to the development of the potent AR antagonist enzalutamide (MDV3100) and the androgen biosynthesis inhibitor abiraterone for treatment of metastatic CRPC [4,5]. They heralded a new era of prostate cancer therapy. Emerging evidences indicate that prostate tumors can adapt to these androgen-directed therapies, including the new agents, by signaling through constitutively-active AR splice variants (AR-Vs) that lack the functional ligand-binding domain [6,7,8,9,10,11,12,13,14,15,16]
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