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

Abstract

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 nonsmall 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-PPAR;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 A (AMPKA), 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 AMPKA 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 AMPKA 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]

Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARγ signaling pathway

“…Subsequently, we found that rosiglitazone enhanced 5-FU-inhibited cell growth of HCC via PPARγ activation, because the effect was completely abrogated by the inactivation of PPARγ through PPARγ siRNA. Han et al have demonstrated that rosiglitazone inhibits nonsmall cell lung cancer (NSCLC) cell growth by both PPARγ-dependent and PPARγ-independent signaling pathways [28] . Our results show that rosiglitazone increases the antitumor effect of 5-FU via the PPARγ-dependent signaling pathway.…”

Peroxisome proliferator-activated receptor γ in bladder cancer: A promising therapeutic target

“…As previously mentioned, rosiglitazone inhibits NSCLC cell proliferation through PPARγ-dependent signals. 54 However, it also occurs by PPARγ-independent signals, as increase in the phosphorylation of AMPKα, which is mediated by rosiglitazone, is not affected by treatment with PPARγ antagonist, GW9662. 54 Recently, Chaffer et al 75 have demonstrated that both PPARγ agonists, TGZ and 15dPGJ2, inhibited prostate and bladder cancer cell growth in a PPARγ-independent fashion.…”

“…54 However, it also occurs by PPARγ-independent signals, as increase in the phosphorylation of AMPKα, which is mediated by rosiglitazone, is not affected by treatment with PPARγ antagonist, GW9662. 54 Recently, Chaffer et al 75 have demonstrated that both PPARγ agonists, TGZ and 15dPGJ2, inhibited prostate and bladder cancer cell growth in a PPARγ-independent fashion. These findings suggest that these anti-tumor effects induced by the PPARγ agonists are attributed to regulation of other various cellular signaling pathways, independently from the PPARγ receptor pathways.…”

“…52,53 In other studies, rosiglitazone reduced phosphorylation of Akt and increased PTEN protein expression in non small-cell lung cancer (NSCLC) cells, and this was associated with inhibition of tumor cell proliferation through PPARγ-dependent signals. 54 PPARγ agonists have also been shown to target cyclin-dependent kinase (CDK) inhibitors such as p18, p21 and p27 during adipogenesis in normal cells and hepatocellular carcinoma cell lines. 55,56 CDK inhibitors block progression of the cell cycle by inactivating the formation of cyclin/CDK complexes, which are crucial for phosphorylation and inactivation of the retinoblastoma protein.…”

PPARγ agonists follow an unknown TRAIL in lung cancer

“…31,[46][47][48] Although the critical mechanisms responsible for biological activity of these ligands are not known, one recent study has shown that rosiglitazone can activate AMP dependent kinase in NSCLC cells in a PPARγ independent manner, which decreases cellular proliferation through inhibition of mTOR. 50 Because mTOR is a kinase downstream of Akt that promotes cellular proliferation and survival, it is possible that the effectiveness of combining PPARγ ligands with TRAIL lies in modulation of multiple pathways that control cellular survival and cell death. The mechanism by which this might occur is a key area that needs to be explored further since this is likely to unveil interesting and important molecular mechanisms modulated by the PPARγ ligands.…”