Anti- and Protumorigenic Effects of PPARγ in Lung Cancer Progression: A Double-Edged Sword
Figure 1
Effector pathways for PPARγ in NSCLC. Antitumorigenic effects of PPARγ on NSCLC cells (top half, shaded): PPARγ-mediated suppression of COX-2 expression in NSCLC leads to decreased PGE2 production, which inhibits NSCLC proliferation. PPARγ can also increase expression and enzymatic activity of PTEN. This leads to inhibition of Akt activation (pAkt), and subsequent decreased activity of the transcription factor NF-κB. NF-κB is a transcription factor that is critical for the production of proangiogenic and proinflammatory cytokines, such as IL-6, IL-8 and VEGF. Decreased production of these factors would be expected to block tumor angiogenesis. PPARγ-mediated suppression of members of the Snail family of transcription factors, such as Snail, Zeb, or Twist, would lead to derepression of E-cadherin expression and promote the epithelial phenotype, leading to decreased migration and invasiveness. Protumorigenic effects of PPARγ on NSCLC cells (bottom half): TGF-induced PPARγ has been shown to bind to Smad3 and p-Smad3, which decreases nuclear accumulation of p-Smad3 and leads to TGF resistance of H460 NSCLC cells. MKK4 depletion in lung cancer cells leads to increased expression of PPARγ and activation of a PPARγ-dependent transcriptional program. Depletion of PPARγ by shRNA in MKK4-depleted lung cancer cells has been shown to reduce invasion in vitro.
