Thiazolidinediones inhibit growth of gastrointestinal, biliary, and pancreatic adenocarcinoma cells through activation of the peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha pathway

Abstract

Peroxisome prolixferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Although previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of several types of tumor cells, the precise mechanism still remains obscure. The present study was designed to examine the effects of PPARgamma/RXRalpha transcriptional activation on cell growth in cancer cells. We compared the effects of six types of TZDs (troglitazone, RS-1303, RS-1330, RS-1387, RS-1455, and RS-1456) and 9-cis RA, an RXRalpha ligand, on the activation of PPARgamma/RXRalpha and the growth inhibition of six types of adenocarcinoma cell lines (MKN45, HT-29, HCT116, HuCCT1, KMP-2, and BxPC3) established from abdominal malignancies. PPARgamma was expressed in all six tumor cell lines and transcriptionally functional in five of the six lines. The stronger PPARgamma activator showed the stronger growth inhibitor in these five cell lines. However, no significant growth inhibitory effect of six types of PPARgamma activators was observed in BxPC3 cells, which showed no significant PPARgamma transactivation by these activators. Simultaneous addition of troglitazone and 9-cis RA enhanced both activation of PPARgamma/RXRalpha and growth inhibition in several types of cancer cells. The degree of PPARgamma/RXRalpha activation correlated with the extent of growth inhibition (r > 0.70, P < 0.05). This growth inhibition was associated with G1 cell cycle arrest and cell differentiation. These findings suggest that activation of the PPARgamma/RXRalpha pathway plays an important role in the growth inhibition of tumor cells and that this nuclear hormone receptor may be a possible novel molecular target for treatment of tumors in humans.