Activated PPAR𝛾 Targets Surface and Intracellular Signals That Inhibit the Proliferation of Lung Carcinoma Cells

Figure 1

Anticancer actions of PPARγ ligands. In addition to genetic abnormalities, lung carcinoma cells receive mitogenic and antiapoptotic signals that promote their progression and metastasis through the activation of key intracellular pathways (e.g., COX-2, Akt, and mTOR). Lung carcinoma cells recognize these signals via diverse receptors for growth factors (e.g., EGFR), prostanoids (e.g., EP2 and EP4), and extracellular matrices (e.g., integrins), among others. In addition, angiogenic factors assist in the vascularization of tumors, while inflammatory signals further promote tumor progression. PPARγ ligands inhibit tumor growth in animal models, but the mechanisms responsible for these effects appear to be multidimensional. In vitro studies reveal that PPARγ ligands affect tumors by inhibiting the expression of key prostanoid and integrin receptors, by reducing the expression of fibronectin, a matrix glycoprotein that stimulates tumor cell proliferation, and by inhibiting the production of angiogenic and inflammatory signals. In addition, PPARγ ligands increase the expression and/or activity of tumor suppressors like PTEN and p21. Although many of these anticancer effects are mediated through PPARγ, others appear to be independent of this nuclear transcription factor (e.g., via targeting TSC2, AMPK, and ROS production and ERK activation, and interacting with CRE, AP-1).