RETRACTED: Activation of Peroxisome Proliferator-Activated Receptor β/δ Induces Lung Cancer Growth via Peroxisome Proliferator-Activated Receptor Coactivatior γ-1α (Retracted Article)

We previously demonstrated that a selective agonist of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta), 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 a (AMPK alpha), a major regulator of energy metabolism. This was mediated through specific activation of PPAR beta/delta, as a PPAR beta/delta small interfering RNA inhibited the effect. However, AMPK alpha did not mediate the growth-promoting effects of GW501516, as silencing of AMPK alpha did not inhibit GW501516-induced cell proliferation. Instead, we found that GW501516 stimulated peroxisome proliferator-activated receptor coactivator gamma (PGC)-1 alpha, which activated the phosphatidylinositol 3 kinase (PI3-K)/Akt mitogenic pathway. An inhibitor of PI3-K, LY294002, had no effect on PGC-1 alpha, consistent with PGC-1 alpha being upstream of PI3-K/Akt. Of note, an activator of AMPK alpha, 5-amino-4-imidazole carboxamide riboside, inhibited the growth-promoting effects of GW501516, suggesting that although AMPK alpha 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 PPAR beta/delta stimulate human lung carcinoma cell proliferation, and suggests that activation of AMPK alpha may oppose this effect.