Vav3-Rac1 Signaling Regulates Prostate Cancer Metastasis with Elevated Vav3 Expression Correlating with Prostate Cancer Progression and Posttreatment Recurrence

Abstract

Prostate cancer remains the second leading cause of cancer death in men in the Western world. Yet current therapies do not significantly improve the long-term survival of patients with distant metastasis. In this study, we investigated the role of the guanine nucleotide exchange factor Vav3 in prostate cancer progression and metastasis and found that Vav3 expression correlated positively with prostate cancer cell migration and invasion. Stimulation of the receptor tyrosine kinase EphA2 by ephrinA1 resulted in recruitment and tyrosine phosphorylation of Vav3, leading to Rac1 activation as well as increased migration and invasion in vitro. Reduction of Vav3 resulted in fewer para-aortic lymph nodes and bone metastasis in vivo. Clinically, expression of Vav3 and EphA2 was elevated in late-stage and metastatic prostate cancers. Among patients with stage IIB or earlier prostate cancer, higher Vav3 expression correlated with lower cumulative biochemical failure-free survival, suggesting that Vav3 may represent a prognostic marker for posttreatment recurrence of prostate cancer. Together, our findings provide evidence that the Vav3-mediated signaling pathway may serve as a therapeutic target for prostate cancer metastasis. Cancer Res; 72(12); 3000-9. Ó2012 AACR.

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

“…Vav3 is overexpressed in human prostate cancer samples versus benign tissue (5). Higher levels of Vav3 were recently demonstrated in metastatic human prostate cancer specimens, and Vav3 expression in primary disease was shown to predict earlier biochemical recurrence (9). Targeting a constitutively active Vav3 allele to prostate epithelium of transgenic mice results in prostate adenocarcinoma development (10).…”

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

“…Although Rac1 as a cytoskeleton organizer has been documented well, more and more recent findings provoked broad functions of Rac1 in human cancers. Rac1 regulates a diverse spectrum of cellular functions including tumorigenesis (11), angiogenesis (12,13) and metastasis (11,14,15). Overexpression of Rac1 occurs in several different types of tumors including breast (16,17), colon (18), bladder (19), and gastric cancer (20,21).…”

“…Rac1 overexpression was observed in metastatic gastric (21), breast (15), prostate (22), bladder upper urinary tract cancer (19). Rac1 promoted prostate cancer progression and recurrence upon activation by VAV3, a GEF for Rac1 activation (14). Rac1 is also involved in sustained cell growth (23) and therapy resistance (24) through crosstalk with other signaling pathways.…”

Phage display discovery of novel molecular targets in glioblastoma-initiating cells

“…Therefore, these molecules require direct validation to determine a potential direct relationship to GICs. We initially chose to primarily focus on VAV3 due its strong negative correlation with patient survival and frequent expression in cancers, including prostate cancer 32 and glioblastoma. 33,34 In five of eight glioma expression databases, elevated VAV3 expression informed statistically significant poor prognosis.…”