Positive inter-regulation between β-catenin/T cell factor-4 signaling and endothelin-1 signaling potentiates proliferation and survival of prostate cancer cells

Both malignant and normal prostate epithelial cells produce endothelin-1 (ET-1), a critical factor in prostate cancer (CaP) progression. beta-Catenin (beta-cat), a key component of the Wnt signaling pathway, is also implicated in CaP progression via beta-cat/T cell factor (Tcf) signaling. We recently demonstrated that beta-cat/Tcf-4 regulates transcription of ET-1 in colon cancer cells. In the present study, we found that Tcf-4 specifically bound to and activated the ET-1 promoter in vivo in human CaP cells and mouse prostate tissue. Expression of ET-1 in DU145 CaP cells was down-regulated by knocking down endogenous beta-cat or Tcf-4. Ectopic activation of beta-cat/Tcf-4 signaling significantly elevated expression of ET-1 in LNCaP cells. In addition, genetic ablation of beta-cat significantly inhibited transcription of ET-1 in primary prostate epithelial cells. Meanwhile, exogenous ET-1 enhanced beta-cat/Tcf signaling and ET-1 expression in DU145 cells, which was blocked by both selective phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)8-phenyl-4H-1-benzopyran-4-one (LY294002) and endothelin-A receptor antagonist cyclo((L)-Leu-(D)-Trp-(D)-Asp-(L)-Pro-(D)-Val) (BQ123). Furthermore, knockdown of either beta-cat or Tcf-4 substantially reduced cell proliferation and potentiated paclitaxel-induced apoptosis in DU145 cells, which largely were rescued by treatment with exogenous ET-1. Together, our results suggest that beta-cat/Tcf-4 signaling transcriptionally activates ET-1 in CaP cells; meanwhile, ET-1 enhances beta-cat/Tcf-4 signaling and in turn further increases ET-1 expression in a PI3K-dependent manner. The positive inter-regulation between beta-cat/Tcf-4 signaling and ET-1 signaling potentiates proliferation and survival of CaP cells, thereby representing a novel mechanism that contributes to CaP progression.