Article Text

PDF
464 WNT 7A AND FZD 9 HAVE AN ANTITUMORIGENIC EFFECT THROUGH ACTIVATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ.
  1. P. Sandoval1,
  2. R. A. Winn1,
  3. M. Van Scoyk1,
  4. K. Rodriguez1
  1. 1Department of Pulmonology and Critical Care Medicine, University of Colorado School of Medicine, Denver, CO

Abstract

The Wnt signaling pathway is critical to normal embryologic development. Mutations that affect Wnt signaling have been seen in carcinomas affecting various organ systems. Our laboratory has previously demonstrated that combined expression of Wnt 7a and Fzd 9 inhibits growth in NSCLC cell lines. Additionally, we have shown that increased expression of peroxisome proliferator-activated receptor γ (PPAR-γ) inhibits transformed growth and promotes epithelial differentiation in NSCLC lines. This study focuses on the role of PPAR-γ in mediating the effects of Wnt 7a and Fzd 9 expression. We found that Wnt 7a and Fzd 9 expression leads to increased PPAR-γ activity. The effect of Wnt 7a and Fzd 9 was not mediated through increased expression of PPAR-γ but rather through activation of ERK5. SR 202, a known PPAR inhibitor, blocked the increase in PPAR activity and restored anchorage-independent growth in NSCLC expressing Wnt 7a and Fzd 9. SR 202 also reversed the increase in E-cadherin expression mediated by Wnt 7a and Fzd 9. Our data suggest that ERK5-dependent activation of PPAR represents a major effector pathway mediating the antitumorigenic effects of Wnt 7a and Fzd 9 in NSCLC. Furthermore, we have shown that Wnt-7a combined with Fzd-9 activates Spry 4, a potent inhibitor of receptor tyrosine kinases (RTK) and growth factors (GF) that are strongly associated with tumorigenesis.

Statistics from Altmetric.com

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.