Vav3 oncogene is overexpressed and regulates cell growth and androgen receptor activity in human prostate cancer.
The purpose of this research was to investigate the role of Vav3 oncogene in human prostate cancer. We found that expression of Vav3 was significantly elevated in androgen-independent LNCaP-AI cells in comparison with that in their androgen-dependent counterparts, LNCaP cells. Vav3 expression was also detected in other human prostate cancer cell lines (PC-3, DU145, and 22Rv1) and, by immunohistochemistry analysis, was detected in 32% (26 of 82) of surgical specimens of human prostate cancer. Knockdown expression of Vav3 by small interfering RNA inhibited growth of both androgen-dependent LNCaP and androgen-independent LNCaP-AI cells. In contrast, overexpression of Vav3 promoted androgen-independent growth of LNCaP cells induced by epidermal growth factor. Overexpression of Vav3 enhanced androgen receptor (AR) activity regardless of the presence or absence of androgen and stimulated the promoters of AR target genes. These effects of Vav3 could be attenuated by either phosphatidylinositol 3-kinase (PI3K) inhibitors or dominant-negative Akt and were enhanced by cotransfection of PI3K. Moreover, phosphorylation of Akt was elevated in LNCaP cells overexpressing Vav3, which could be blocked by PI3K inhibitors. Finally, we ascertained that the DH domain of Vav3 was responsible for activation of AR. Taken together, our data show that overexpression of Vav3, through the PI3K-Akt pathway, inappropriately activates AR signaling axis and stimulates cell growth in prostate cancer cells. These findings suggest that Vav3 overexpression may be involved in prostate cancer development and progression.
Dong
Zhongyun
Z
Department of Pathology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, Ohio 45267, USA.
Liu
Yin
Y
Lu
Shan
S
Wang
Amy
A
Lee
Kiwon
K
Wang
Lu-Hai
LH
Revelo
Monica
M
Lu
Shan
S
D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010957:Plasmids / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C496621:VAV3 protein, human