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

Abstract

Peroxisome prolixferator-activated receptor γ (PPARγ), a ligand-activated transcription factor, forms a heterodimer with retinoid X receptor α (RXRα), and its transcriptional activity is thought to be maximal in the presence of both PPARγ and RXRα ligands. Although previous studies suggested that thiazolidinediones (TZDs), known as PPARγ 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 PPARγ/RXRα 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 RXRα ligand, on the activation of PPARγ/RXRα and the growth inhibition of six types of adenocarcinoma cell lines (MKN45, HT-29, HCT116, HuCCT1, KMP-2, and BxPC3) established from abdominal malignancies. PPARγ was expressed in all six tumor cell lines and transcriptionally functional in five of the six lines. The stronger PPARγ activator showed the stronger growth inhibitor in these five cell lines. However, no significant growth inhibitory effect of six types of PPARγ activators was observed in BxPC3 cells, which showed no significant PPARγ transactivation by these activators. Simultaneous addition of troglitazone and 9- cis RA enhanced both activation of PPARγ/RXRα and growth inhibition in several types of cancer cells. The degree of PPARγ/RXRα 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 PPARγ/RXRα 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.