Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor- Ligands in Lung Cancer
Figure 2
Effector
pathways for PPAR in NSCLC. PPAR can increase either expression of enzymatic activity of PTEN.
This results in inhibition of Akt activation (pAkt), which may be involved in
the growth inhibitory responses seen with PPAR activation. Decreased Akt
activity also can lead to decreased activity of the transcription factor NF-κB. NF-κB is a critical transcription factor in the production of
proangiogenic and proinflammatory cytokines such as VEGF, IL-8. Decreased production of these factors would
be expected to inhibit recruitment of inflammatory cells such as macrophages,
and block tumor angiogenesis. PPAR-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.
PPAR-mediated suppression of COX-2 expression in NSCLC has been shown
by several investigators. This would
result in decreased production, which will impact growth. TZDs can inhibit production
through a PPAR-independent pathway involving induction of 15-hydroxyprostaglandin
dehydrogenase (PGDH). Pathways indicated in green are
increased or activated by PPAR, while those in red represent pathways that are
inhibited or repressed.
