Abstract
2680
Androgen is known to be a key mitogen factor for the growth of prostate cancer. Androgenic effect is mediated through its specific receptor as a transcription factor. However, recent studies indicate that androgen receptor (AR) can function via non-genomic pathway by activating non-receptor tyrosine kinase such as Src and subsequent down stream signal pathway such as MAPK, which results in cell proliferation of prostate cancer (PCa). In PCa, DOC-2/DAB2 appears to be a potent tumor suppressor in prostate by directly inhibiting the function of several signaling molecules containing SH3 domain including Grb2 and Src. Thus, we decided to investigate the effect of DOC-2/DAB2 on AR-mediated signal transduction in PCa. Previous data demonstrate that the treatment of Src inhibitor can suppress the androgen-induced cell proliferation in LNCaP cell line, indicating that the Src activation is involved in the AR-mediated cell proliferation. Also, the inhibition on the AR-mediated cell proliferation of LNCaP subline was found in cells transfected with DOC-2/DAB2. On the other hand, we studied a normal human prostate cell line PZ-HPV7 expressing endogenous DOC-2/DAB2 protein and AR and we found that the proliferation of PZ-HPV7 cell could be stimulated by androgen in a dose-dependent manner. By transfecting PZ-HPV7 with an interference RNA targeting DOC-2/DAB2 mRNA specifically, we observed a further enhancement of AR-induced cell proliferation in this cell line. The data indicate that DOC-2/DAB2 plays a central role in modulating AR effect in normal prostatic epithelium. To understand the underlying mechanism, we were able to demonstrate that the AR-induced activation of Src, determined by a specific anti-phosphorylated Src (tyrosine416) antibody, which could be suppressed in PCa cells expressing DOC-2/DAB2 protein. Subsequently, the down stream MAPK pathway such as Erk2 was also suppressed by DOC-2/DAB2. To demonstrate the interruption between the physical interaction of Src protein and AR by DOC-2/DAB2, a pull-down experiment was conducted using GST-Src (SH3 domain) fusion protein in which the interaction between AR and Src could be blocked by an increasing amount of DOC-2/DAB2. To examine whether DOC-2/DAB2 could modulate the transcription activity of AR, we found that DOC-2/DAB2 did not the promoter activity of PSA induced by androgen. Thus, our data demonstrate that DOC-2/DAB2 can modulate the AR-induced cell proliferation in PCa via the non-genomic pathway of AR by competing the binding to Src. Taken together, we believe that DOC-2/DAB2 is a key homeostatic factor to balance the mitogenic signal in normal prostatic epithelium.
- American Association for Cancer Research
Volume 64, Issue 7 Supplement
