The molecular mechanism of Vav3 oncogene on upregulation of androgen receptor activity in prostate cancer cells.
Our previous studies revealed that Vav3 oncogene is overexpressed in human prostate cancer, enhances androgen receptor (AR)-mediated signaling, and may play a role in prostate cancer development and progression. The purpose of this study was to determine the molecular mechanisms responsible for AR activation by Vav3. We found that interaction between N-terminus and C-terminus of AR is essential for its elevated activity stimulated by Vav3. The DH and PH domains of Vav3 are involved in direct interaction with AR. Both cytoplasmic and nuclear levels of AR and Vav3 are elevated and their nuclear localization is further stimulated by DHT in androgen-independent LNCaP-AI cells relative to their parental androgen-dependent LNCaP cells. Vav3 is colocalized with AR, phospho(P)-Akt, and HER2 with a short term stimulation by EGF and DHT. PI3K inhibitor LY294002 blocks colocalization of Vav3 with P-Akt. Consistently, EGF and DHT stimulate Vav3 and AR interaction and enhance PI3K-Akt signaling. Mutation of tyrosines to phenylalanines in the acidic domain or deletion of the SH2 and SH3 domains significantly enhances Vav3 ability for AR activation, while deletion of the DH domain abolishes this activity. Given that an elevated interaction of Vav3 with AR, P-Akt, and HER2 in both cytoplasm and nucleus upon the short-term of DHT stimulation, our data suggest that Vav3 may enhance non-genomic AR activity via PI3K-Akt signaling in addition to AR transcriptional activity and further support a role in androgen-independent growth in prostate cancer.
Liu
Yin
Y
Department of Pathology, University of Cincinnati College of Medicine, the Metabolic Diseases Institute, Cincinnati, OH 45237, USA.
Wu
Xiaoyang
X
Dong
Zhongyun
Z
Lu
Shan
S
D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008297:Male; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051567:Proto-Oncogene Proteins c-vav / Q000096:biosynthesis*; D011944:Receptors, Androgen / Q000096:biosynthesis*; D015398:Signal Transduction
C410798:AR protein, human; D051567:Proto-Oncogene Proteins c-vav; D011944:Receptors, Androgen; C496621:VAV3 protein, human