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 gamma.
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 gamma (PPARgamma) 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 PPARgamma. We found that Wnt 7a and Fzd 9 expression led to increased PPARgamma 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 PPARgamma activation in NSCLC. SR 202, a known PPARgamma inhibitor, blocked the increase in PPARgamma 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 PPARgamma represents a major effector pathway mediating the anti-tumorigenic effects of Wnt 7a and Fzd 9 in NSCLC.
Winn
Robert A
RA
Veterans Administration Medical Center, Denver, and Department of Medicine, University of Colorado Health Sciences Center, 80220, USA. robert.winn@uchsc.edu
Van Scoyk
Michelle
M
Hammond
Mandy
M
Rodriguez
Karen
K
Crossno
Joseph T
JT
Heasley
Lynn E
LE
Nemenoff
Raphael A
RA
D000970:Antineoplastic Agents / Q000494:pharmacology; D015820:Cadherins / Q000096:biosynthesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D051157:Frizzled Receptors / Q000737:chemistry / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000502:physiology*; D017981:Receptors, Neurotransmitter / Q000378:metabolism / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D015820:Cadherins; C105574:FZD3 protein, human; D051157:Frizzled Receptors; D009943:Organophosphorus Compounds; D047495:PPAR gamma; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; C092778:WNT7A protein, human; D051153:Wnt Proteins; D048054:Mitogen-Activated Protein Kinase 7; C051602:mifobate