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¹ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine and ² Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

Requests for reprints: ShouWei Han, 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. Phone: 404-712-2661; Fax: 404-712-2151. E-mail: shan2{at}emory.edu

Peroxisome proliferator-activated receptors (PPAR) exert diverse effects on cancer cells. Recent studies showed that rosiglitazone, a synthetic ligand for PPAR, inhibits cell growth. However, the exact mechanisms underlying this effect are still being explored, and the relevance of these findings to lung cancer remains unclear. Here, we report that rosiglitazone reduced the phosphorylation of Akt and increased phosphatase and tensin homologue (PTEN) protein expression in non–small cell lung carcinoma (NSCLC) cells (H1792 and H1838), and this was associated with inhibition of NSCLC cell proliferation. These effects were blocked or diminished by GW9662, a specific PPAR antagonist. However, transfection with a CMX-PPAR2 overexpression vector restored the effects of rosiglitazone on Akt, PTEN, and cell growth in the presence of GW9662. In addition, rosiglitazone increased the phosphorylation of AMP-activated protein kinase (AMPK), a downstream kinase target for LKB1, whereas it decreased phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream target of mammalian target of rapamycin (mTOR). Of note, GW9662 did not affect the phosphorylation of AMPK and p70S6K protein. The inhibitory effect of rosiglitazone on NSCLC cell growth was enhanced by the mTOR inhibitor rapamycin; however, it was blocked, in part, by the AMPK small interfering RNA. Taken together, these findings show that rosiglitazone, via up-regulation of the PTEN/AMPK and down-regulation of the Akt/mTOR/p70S6K signal cascades, inhibits NSCLC cell proliferation through PPAR-dependent and PPAR-independent signals. [Mol Cancer Ther 2006;5(2):430–7]

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Received 8/29/05; revised 11/ 9/05; accepted 12/ 8/05.

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