Vav3 enhances androgen receptor splice variant activity and is critical for castration-resistant prostate cancer growth and survival

Stephanie O. Peacock, Cale D. Fahrenholtz, Kerry L. Burnstein

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Advanced or metastatic prostate cancer is treated by androgen deprivation; however, patients inevitably relapse with castration-resistant prostate cancer (CRPC). CRPC remains dependent on androgen receptor (AR) signaling, which may include constitutive, ligand-independent action of naturally occurring AR splice variants. For example, the AR splice variant AR3 (also termed AR-V7) is expressed in CRPC and is linked to poor prognosis. Vav3, aRhoGTPase guanine nucleotide exchange factor, is anAR coactivator that is up-regulated in human prostate cancer compared with benign tissue and in preclinical models of CRPC. Vav3 confers castration-resistant growth to androgen-dependent human prostate cancer cells. Despite the importance of AR coactivators in promoting CRPC, the potential role of these regulatory proteins in modulating AR splice variant activity is unknown. We examined the contributions of Vav3 to AR activity in two CRPC cell lines that naturally express relatively high levels of Vav3 and AR3. Vav3 or AR3 knockdown greatly attenuated cell proliferation, soft agar growth, and ligand-independent AR activity. Vav3 potently enhanced the transcriptional activity of AR3 and another clinically relevantARsplice variant, ARv567es. Vav3 knockdown resulted in lowered nuclear AR3 levels, whereas total AR3 levels remained similar. Conversely, overexpression of Vav3 resulted in increased nuclear AR3. Coimmunoprecipitation revealed that AR3 and Vav3 interact. These novel data demonstrating physical and functional interactions between Vav3, a uniqueARcoactivator, and anAR splice variant provide insights into the mechanisms by which Vav3 exploits and enhances AR signaling in the progression to CRPC.

Original languageEnglish (US)
Pages (from-to)1967-1979
Number of pages13
JournalMolecular Endocrinology
Volume26
Issue number12
DOIs
StatePublished - Dec 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Fingerprint Dive into the research topics of 'Vav3 enhances androgen receptor splice variant activity and is critical for castration-resistant prostate cancer growth and survival'. Together they form a unique fingerprint.

  • Cite this