Vav3/Rac1 Signaling Promotes Castration-Resistant Prostate Cancer

Objectives. To define more clearly the role of Vav3 in the progression to castration resistant prostate cancer( CRPC). Background. Increased androgen receptor (AR) transcriptional activity drives growth of castration-resistant prostate cancer (CRPC). This enhanced AR activity is due to different mechanisms, including increased levels of AR coactivator proteins and ligand-independent activation of AR by growth factor-initiated signaling. We and others have shown that Vav3, a growth factor-activated Rho GTPase guanine nucleotide exchange factor (GEF), is up-regulated in cell and mouse models of CRPC and in a large proportion of primary prostate cancer clinical specimens. Methods. These studies used cell imaging of human prostate cancer cell lines, tumor xenograft models , three-dimensional protein modeling, and biochemical and molecular approaches. Results. We found that Vav3 activates the Rho GTPase, Rac1, in prostate cancer cells. Further, expression of wild type Vav3 or a constitutively active Rac1 mutant was sufficient for robust castration-resistant xenograft tumor growth. Further, Vav3 potentiates AR activity in the presence of very low androgen concentrations, in a PH dependent, yet GEF independent manner. We found that Vav3 nuclear localization is important to its coactivator function, and sequential chromatin immunoprecipitation experiments revealed that Vav3 and AR were simultaneously recruited to the same transcriptional complexes. Conclusions. Vav3 and Rac1 signaling pathways can act in concert to drive AR transcriptional activity and prostate cancer progression. These studies suggest a Key role for Vav3/Rac1 in CRPC progression and support therapeutic disruption of this signaling pathway.