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

¹ Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; ² Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China; and ³ Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to ShouWei Han, M.D., Ph.D., Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Whitehead Bioresearch Building, 615 Michael Street, Suite 205-M, Atlanta, GA 30322. E-mail: shan2{at}emory.edu

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

Key Words: peroxisome proliferator–activated receptor-β/ • AMP-activated protein kinase- • peroxisome proliferator–activated receptor coactivator-–1 • phosphatidylinositol 3 kinase/Akt • human lung carcinoma cells

CLINICAL RELEVANCE This study highlights the possibility of modulating peroxisome proliferator–activated receptor (PPAR) β/ pathways to inhibit lung cancer cell growth. Further studies testing the role of blocking PPARβ while stimulating AMP-activated protein kinase may show an enhanced therapeutic efficacy against lung cancer.