Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy.

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.

• Authors: Bo Cao, Yanfeng Qi, Guanyi Zhang, Duo Xu, Yang Zhan, Xavier Alvarez, Zhiyong Guo, Xueqi Fu, Stephen R Plymate, Oliver Sartor, Haitao Zhang, Yan Dong
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 6 Pg. 1646-56 (Mar 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24722067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AR protein, human
• Androgens
• Benzamides
• Nitriles
• Protein Isoforms
• RNA, Messenger
• Receptors, Androgen
• Phenylthiohydantoin
• enzalutamide

Topics

• Androgens (pharmacology)
• Animals
• Apoptosis (drug effects)
• Benzamides
• Cell Nucleus (metabolism)
• Cell Proliferation (drug effects)
• Chromatin Immunoprecipitation
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasms, Hormone-Dependent (drug therapy, genetics, pathology)
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Promoter Regions, Genetic (genetics)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Protein Isoforms
• Protein Transport (drug effects)
• RNA Splicing (genetics)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Androgen (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Subcellular Fractions
• Transcriptional Activation
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays