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.
Highlights
The Vav3 oncogene, the third member of the Vav family of Rho GTPase nucleotide exchange factors (GEF; refs. 1–3), is involved in various cellular signaling processes, acting through its classical Dbl domain to activate the Rho family GTPases, including RhoA, Rac1, and Cdc42 [3, 4]
Subsequent analyses evaluated the possible association of migration/invasion with Vav3 expression, observing that both migration and invasion occurred to significantly greater extents in the high Vav3-expressing cells (C4-2 and PC3) than in the low Vav3-expressing LNCaP cells (Fig. 1C and D)
The present study indicates the significance of receptor tyrosine kinases (RTK)-mediated activation of Vav3, especially the EphA2-Vav3-Rac1 signaling axis, in prostate cancer metastasis
Summary
The Vav oncogene, the third member of the Vav family of Rho GTPase nucleotide exchange factors (GEF; refs. 1–3), is involved in various cellular signaling processes, acting through its classical Dbl domain to activate the Rho family GTPases, including RhoA, Rac, and Cdc42 [3, 4]. The Vav oncogene, the third member of the Vav family of Rho GTPase nucleotide exchange factors 1–3), is involved in various cellular signaling processes, acting through its classical Dbl domain to activate the Rho family GTPases, including RhoA, Rac, and Cdc42 [3, 4]. Various receptor tyrosine kinases (RTK) activate Vav proteins [3, 5], resulting in the opening up of the Dbl domain for its substrate [6]. The Eph receptors are the largest family of RTKs and have significant roles in the regulation of cell attachment, cell shape, and motility during development and pathologic conditions, especially cancer metastases [10,11,12]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Authors' Affiliations: 1Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan; 2Department of Pharmacology, College of Physicians and Surgeons, Columbia University; 3Department of Microbiology, Mount Sinai School of Medicine, New York; and 4Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
