Positive inter-regulation between beta-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.
Sun
Ping
P
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Xiong
Hui
H
Kim
Tae Hoon
TH
Ren
Bing
B
Zhang
Zhuohua
Z
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051820:TCF Transcription Factors; D013936:Thymidine; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse