Activation of Peroxisome Proliferator–Activated Receptor β/δ Induces Lung Cancer Growth via Peroxisome Proliferator–Activated Receptor Coactivator γ-1α

摘要

We previously demonstrated that a selective agonist of peroxisome proliferator–activated receptor β/δ (PPARβ/δ), GW501516, stimulated human non–small cell lung carcinoma (NSCLC) growth, partly through inhibition of phosphatase and tensin homolog deleted on chromosome 10 expression. Here, we show that GW501516 also decreases the phosphorylation of AMP-activated protein kinase α (AMPKα), a major regulator of energy metabolism. This was mediated through specific activation of PPARβ/δ, as a PPARβ/δ small interfering RNA inhibited the effect. However, AMPKα did not mediate the growth-promoting effects of GW501516, as silencing of AMPKα did not inhibit GW501516-induced cell proliferation. Instead, we found that GW501516 stimulated peroxisome proliferator–activated receptor coactivator γ (PGC)-1α, which activated the phosphatidylinositol 3 kinase (PI3-K)/Akt mitogenic pathway. An inhibitor of PI3-K, LY294002, had no effect on PGC-1α, consistent with PGC-1α being upstream of PI3-K/Akt. Of note, an activator of AMPKα, 5-amino-4-imidazole carboxamide riboside, inhibited the growth-promoting effects of GW501516, suggesting that although AMPKα is not responsible for the mitogenic effects of GW501516, its activation can oppose these events. This study unveils a novel mechanism by which GW501516 and activation of PPARβ/δ stimulate human lung carcinoma cell proliferation, and suggests that activation of AMPKα may oppose this effect.