Ligands for peroxisome proliferator-activated receptor γ inhibit growth of pancreatic cancers both in vitro and in vivo

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is expressed largely in adipose tissues and plays an important role in adipocyte differentiation. Several studies have recently shown that ligands of PPAR gamma could lead to growth inhibition in some malignancies. In our study, we focused on pancreatic cancers, because the prognosis of advanced pancreatic cancer has not significantly improved due to its resistance to various chemotherapeutic regimens, so that a novel strategy should be required. We show here that PPAR gamma is expressed in 5 pancreatic cancer cell lines detected in both mRNA and protein level as well as in human primary and metastatic pancreatic carcinomas examined by immunohistochemical studies. A specific ligand of PPAR gamma, troglitazone, led to G1 accumulation with the increase in p27(KipI), but not p21(Waf1/Cip1) and inhibited cellular proliferation in a pancreatic cancer cell line, Panc-1. The overexpression of PPAR gamma in a pancreatic cancer cell line, KMP-3, caused lipid accumulation, which suggested cell growth in some cancers might be inhibited, at least in part, through terminal differentiation in the adipogenic lineage. In addition, implanted Panc-1 tumors in nude mice showed significant inhibition of tumor growth, when treated with pioglitazone, another specific ligand of PPAR gamma. Our results suggest that ligands of PPAR gamma may be a novel therapeutic agent for the treatment of pancreatic carcinomas. (C) 2001 Wiley-Liss, Inc.