Accession Number:

ADA574854

Title:

Hic-5's Regulatory Role in TGFB Signaling in Prostate Stroma

Descriptive Note:

Annual summary rept. 1 Jul 2009-30 Jun 2012

Corporate Author:

PITTSBURGH UNIV PA

Personal Author(s):

Report Date:

2012-06-01

Pagination or Media Count:

49.0

Abstract:

The tumor microenvironment plays a critical role in supporting cancer cells particularly as they disengage from limitations on their growth and motility imposed by surrounding nonreactive stromal cells. We show here that stromal-derived androgenic precursors are metabolized by DU145 human prostate cancer PCa cells to generate ligands for ER , which acts to limit their motility through transcriptional regulation of E-cadherin. While primary human PCa-associated fibroblasts and the human WPMY-1 reactive prostate stromal cell line maintain this inherent ER -dependent motility inhibitor activity, they are subverted by TGF- 1 pro-oxidant signals derived from co-cultured DU145 PCa cells. Specifically, stromal-produced H2O2, which requires Cox-2, acts as a second paracrine factor to inhibit ER activity in adjacent DU145 cells. ChIP analysis reveals that ER recruitment to the E-cadherin promoter is inhibited when H2O2 is present. Both neutralization of H2O2 with catalase and prevention of its production by silencing Cox-2 expression in stromal cells restore the motility-suppression activity of stromal-derived ER ligand precursors. These data suggest that reactive stromal cells may still have a capacity to limit cancer cell motility through a local endocrine network but must be protected from pro-oxidant signals triggered by cancer cell derived TGF- 1 to exhibit this cancer suppressive function.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE