Rosiglitazone suppresses human lung carcinoma cell growth through PPAR-γ-dependent and PPARγ-independent signal pathways

被引:147
作者
Han, SW
Roman, J
机构
[1] Emory Univ, Sch Med, Div Pulm Allergy & Crit Care Med, Dept Med, Atlanta, GA 30322 USA
[2] Atlanta Vet Affairs Med Ctr, Atlanta, GA USA
关键词
D O I
10.1158/1535-7163.MCT-05-0347
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Peroxisome proliferator-activated receptors gamma (PPAR gamma) exert diverse effects on cancer cells. Recent studies showed that rosiglitazone, a synthetic ligand for PPAR gamma, 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 gamma antagonist. However, transfection with a CMX-PPAR gamma 2 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 alpha (AMPK alpha), 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 alpha 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 alpha 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 gamma-dependent and PPAR gamma-independent signals.
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收藏
页码:430 / 437
页数:8
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