title: Growth inhibition of pancreatic cancer cells through activation of peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha pathway.
abstract: Peroxisome proliferator-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. Though previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of certain types of cancer cells, little is known about the growth inhibitory effects mediated though activation of PPARgamma/RXRalpha. We examined the effects of troglitazone (one type of TZDs) and 9-cis retinoic acid, a RXRalpha ligand, on activation of PPARgamma/RXRalpha and growth inhibition of human pancreatic cancer cell lines (AsPC1, BxPC3, PSN1, PCI6, Panc1, KMP-4, and KMP-7). Combined treatment of troglitazone and 9-cis retinoic acid showed enhanced transcriptional activity and enhanced antiproliferative effects. In PSN1 cells, G1 cell cycle arrest and apoptosis were induced by troglitazone and these effects were enhanced with additional 9-cis RA. Our findings suggest that activation of PPARgamma/RXRalpha pathway might play an important role in growth inhibition of pancreatic cancer cells via G1 cell cycle arrest and apoptosis. This nuclear receptor might be a suitable molecular target for treatment of pancreatic cancers.
authors.affiliation: Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tsujie
authors.forename: Shoji
authors.initials: S
authors.lastname: Nakamori
authors.forename: Jiro
authors.initials: J
authors.lastname: Okami
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Hayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.forename: Keizo
authors.initials: K
authors.lastname: Dono
authors.forename: Koji
authors.initials: K
authors.lastname: Umeshita
authors.forename: Masato
authors.initials: M
authors.lastname: Sakon
authors.forename: Morito
authors.initials: M
authors.lastname: Monden
mesh_terms: D000077556:Alitretinoin; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D009687:Nuclear Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D000077288:Troglitazone; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
chemical_list: D002839:Chromans; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1; D000077556:Alitretinoin; D014212:Tretinoin; D000077288:Troglitazone