Peroxisome proliferator-activated receptor γ (PPARγ) plays a critical role in the development of TGFβ resistance of H460 cell

The primary goal of the study was to investigate how peroxisome proliferator-activated receptor gamma (PPAR gamma) played a critical role in the protection of H460 cell, one of the non-small cell lung cancer (NSCLC) cells with multidrug resistance, from transforming growth factor beta (TGF beta)-mediated mitoinhibition. In the study. TGF beta resistance of H460 cell was first confirmed by analyses of PPAR gamma expression, its interaction with TGF beta-induced Smad3 and phospho-Smad3 (p-Smad3) and survival of H460. Results showed that enable to escape from G2/M phase arrest. H460 cell had higher resistance to TGF beta-mediated mitoinhibition than CH27 (a drug sensitive control). TGF beta significantly increased PPAR gamma expression of H460 but not of CH27 cell whereas nuclear accumulation of p-Smad3 was only limited to CH27, the latter was believed to contribute to the induction P-21 (waf1/cip1) and cyclin B1, cell cycle arrest at G2/M phase and TGF beta-mediated mitoinhibition of CH27 cell. TGF beta-incluced PPAR gamma of H460 cell was further demonstrated to bind to Smad3 and p-Smad3, and GW9662 (PPAR gamma inhibitor) or PPAR gamma-specific shRNA could disrupt the binding. GW9662 also increased the nuclear accumulation of p-Smad3 that eventually led to the reduction of TGF beta resistance of H460. A transient knockdown of PPAR gamma with shRNA revealed a similar effect as GW9662. In addition, activation of P-38 instead of ERK played a critical role in TGF beta-induced expression of PPAR gamma. which subsequently activated RhoA in H460 cell. (C) 2011 Elsevier Inc. All rights reserved.