Both β-catenin (β-cat) and endothelin-1 (ET-1) play important roles in progression of prostate cancer (CaP). Increased secretion of ET-1 and activation of β-cat/TCF signaling are associated with advanced prostate cancer. We have recently demonstrated that β-cat/TCF-4 regulates ET-1 expression in colon cancer cells. In the present study, we showed that β-cat/TCF-4 specifically binds to the ET-1 promoter in DU145 CaP cells and mouse prostate tissue. Expression of ET-1 in DU145 cells was remarkably down-regulated by knockdown of endogenous β-cat or TCF-4 expression with retrovirus-mediated RNA interference. Moreover, deletion of the β-cat gene also significantly inhibited the ET-1 expression in mouse primary prostate epithelial cell cultures. Furthermore, knockdown of either β-catenin or TCF-4 in DU145 cells substantially reduced [3H]-thymidine incorporation and potentiated susceptibility to paclitaxel-induced apoptosis. These effects were to a great extent rescued by exogenous ET-1. Together, our results suggest that β-cat/TCF-4 signaling promotes proliferation and survival of CaP cells via transcriptional activation of ET-1 and reveal a novel mechanism of β-cat/TCF signaling in regulating CaP progression. (This work is supported by a grant from Department of Defense, Prostate Cancer Research Program).
[Proc Amer Assoc Cancer Res, Volume 46, 2005]