QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Erratum An erratum has been published All Versions of this Article: mol.105.019620v1 69/2/520    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sun, P. Articles by Zhang, Z. Search for Related Content PubMed PubMed Citation Articles by Sun, P. Articles by Zhang, Z.

Positive Inter-Regulation between -Catenin/T Cell Factor-4 Signaling and Endothelin-1 Signaling Potentiates Proliferation and Survival of Prostate Cancer Cells

Burnham Institute for Medical Research, La Jolla, California (P.S., H.X., Z.Z.); and Ludwig Institute for Cancer Research, and Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, California (T.H.K., B.R.)

Both malignant and normal prostate epithelial cells produce endothelin-1 (ET-1), a critical factor in prostate cancer (CaP) progression. -Catenin (-cat), a key component of the Wnt signaling pathway, is also implicated in CaP progression via -cat/T cell factor (Tcf) signaling. We recently demonstrated that -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 -cat or Tcf-4. Ectopic activation of -cat/Tcf-4 signaling significantly elevated expression of ET-1 in LNCaP cells. In addition, genetic ablation of -cat significantly inhibited transcription of ET-1 in primary prostate epithelial cells. Meanwhile, exogenous ET-1 enhanced -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 -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 -cat/Tcf-4 signaling transcriptionally activates ET-1 in CaP cells; meanwhile, ET-1 enhances -cat/Tcf-4 signaling and in turn further increases ET-1 expression in a PI3K-dependent manner. The positive inter-regulation between -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.

Received for publication October 5, 2005.

Accepted for publication November 15, 2005.

Address correspondence to: Zhuohua Zhang, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail: benzz{at}burnham.org.

This article has been cited by other articles:

				A. R. Folsom, J. S. Pankow, J. M. Peacock, S. J. Bielinski, G. Heiss, and E. Boerwinkle Variation in TCF7L2 and Increased Risk of Colon Cancer: The Atherosclerosis Risk in Communities (ARIC) Study Diabetes Care, May 1, 2008; 31(5): 905 - 909. [Abstract] [Full Text] [PDF]