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J. Biol. Chem., Vol. 281, Issue 37, 26943-26950, September 15, 2006

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Antitumorigenic Effect of Wnt 7a and Fzd 9 in Non-small Cell Lung Cancer Cells Is Mediated through ERK-5-dependent Activation of Peroxisome Proliferator-activated Receptor ^*

Robert A. Winn¹, Michelle Van Scoyk, Mandy Hammond, Karen Rodriguez, Joseph T. Crossno, Jr., Lynn E. Heasley, and Raphael A. Nemenoff

From the Veterans Administration Medical Center, Denver, Colorado 80220 and the Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262

The Wnt pathway is critical for normal development, and mutation of specific components is seen in carcinomas of diverse origins. The role of this pathway in lung tumorigenesis has not been clearly established. Recent studies from our laboratory indicate that combined expression of the combination of Wnt 7a and Frizzled 9 (Fzd 9) in Non-small Cell Lung Cancer (NSCLC) cell lines inhibits transformed growth. We have also shown that increased expression of peroxisome proliferator-activated receptor (PPAR) inhibits transformed growth of NSCLC and promotes epithelial differentiation of these cells. The goal of this study was to determine whether the effects of Wnt 7a/Fzd 9 were mediated through PPAR. We found that Wnt 7a and Fzd 9 expression led to increased PPAR activity. This effect was not mediated by altered expression of the protein. Wnt 7a and Fzd 9 expression resulted in activation of ERK5, which was required for PPAR activation in NSCLC. 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. These data suggest that ERK5-dependent activation of PPAR represents a major effector pathway mediating the anti-tumorigenic effects of Wnt 7a and Fzd 9 in NSCLC.

Received for publication, May 1, 2006 , and in revised form, July 10, 2006.

^* This work was supported by an Advanced Veterans Administration Career Development grant, a Lung SPORE Career Development National Institutes of Health grant, and additional grants from the National Institutes of Health (CA103618, CA108610, and CA58187). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262. Tel.: 303-315-0011; Fax: 303-315-4852; E-mail: robert.winn{at}uchsc.edu.

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