Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC)

Pharmacological activators of peroxisome proliferatoractivated receptor-gamma (PPARgamma) have been shown to inhibit growth of lung tumors largely through growth inhibition and induction of apopotosis. However, since many of these agents engage other effectors, the role of PPARgamma in lung tumorigenesis remains poorly defined. To specifically examine PPARgamma-mediated events, non-small-cell lung cancer (NSCLC) cells overexpressing PPARgamma were established. Overexpression of PPARgamma in H2122 adenocarcinoma cells (H2122-PPARgamma) blocked anchorage-independent growth compared to cells transfected with empty vector (H2122-LNCX), but had no significant effect on cell proliferation or apoptosis under standard tissue culture conditions. Orthotopic implantation of H2122-PPARgamma cells into the lungs of nude rats inhibited tumor growth and metastasis in vivo and prolonged survival compared to implantation of H2122-LNCX cells. Consistent with these findings, H2122-PPARgamma cells had an impaired invasiveness as assessed in Transwell assays. In a three-dimensional culture system, H2122-PPARgamma cells formed polarized spheroid structures similar to those observed with normal lung epithelial cells. H2122-LNCX cells formed nonpolarized aggregate structures and did not show any of these epithelial properties. These data indicate that inhibitory effects of PPARgamma on lung tumorigenesis involve selective inhibition of invasive metastasis, and activation of pathways that promote a more differentiated epithelial phenotype.