RRC ID 42095
Author Leung WK, Bai AH, Chan VY, Yu J, Chan MW, To KF, Wu JR, Chan KK, Fu YG, Chan FK, Sung JJ.
Title Effect of peroxisome proliferator activated receptor gamma ligands on growth and gene expression profiles of gastric cancer cells.
Journal Gut
Abstract BACKGROUND AND AIMS:Although peroxisome proliferator activated receptor gamma (PPARgamma) agonists have been implicated in differentiation and growth inhibition of cancer cells, the potential therapeutic and chemopreventive effects on gastric cancer are poorly defined. We examined the in vitro and in vivo effects of PPARgamma ligands on growth of gastric cancer, and the effect of PPARgamma activation on expression of cyclooxygenase 2 (COX-2) and cancer related genes.
METHODS:Gastric cell lines (MKN28 and MKN45) were treated with two specific PPARgamma ligands: ciglitazone and 15-deoxy-Delta(12,)(14)-prostaglandin J(2). Cell growth was determined by bromodeoxyuridine incorporation assay and apoptosis was measured by DNA fragmentation. Expression of COX-2 was determined by western blot and real time quantitative polymerase chain reaction (PCR). Expression profiles of cancer related genes were screened with cDNA array. In vivo growth of implanted MKN45 cells in nude mice was monitored after oral treatment with rosiglitazone.
RESULTS:PPARgamma ligands suppressed the in vitro growth of MKN45 cells in a dose dependent manner whereas prostacyclin, a PPARdelta agonist, had no growth inhibitory effect. Growth inhibition was more pronounced in MKN45 cells, which was accompanied by DNA fragmentation and downregulation of COX-2. Screening by cDNA microarray showed that PPARgamma ligand treatment was associated with upregulation of bad and p53, and downregulation of bcl-2, bcl-xl, and cyclin E1 in MKN45 cells, which was confirmed by quantitative real time PCR. In contrast, MKN28 cells with lower PPARgamma and COX-2 expression levels had lower growth inhibitory responses to PPARgamma ligands. Microarray experiments only showed induction of the bad gene in MKN28 cells. In vivo growth of MKN45 cells in nude mice was retarded by rosiglitazone. Mean tumour volume in rosiglitazone treated mice was significantly lower than controls at six weeks (p = 0.019) and seven weeks (p = 0.001) after treatment.
CONCLUSIONS:PPARgamma ligands suppress both in vitro and in vivo growth of gastric cancer and may play a major role in cancer therapy and prevention.
Volume 53(3)
Pages 331-8
Published 2004-3
DOI 10.1136/gut.2003.021105
PMID 14960510
PMC PMC1773979
MeSH Animals Antineoplastic Agents / therapeutic use Apoptosis / drug effects Cell Division / drug effects Cyclooxygenase 2 Dose-Response Relationship, Drug Gene Expression Regulation, Neoplastic* / drug effects Humans Intracellular Signaling Peptides and Proteins* Isoenzymes / metabolism Ligands Male Membrane Proteins Mice Mice, Inbred BALB C Mice, Nude Neoplasm Proteins / physiology* Neoplasm Transplantation Nuclear Receptor Coactivators Prostaglandin D2 / analogs & derivatives* Prostaglandin D2 / pharmacology Prostaglandin-Endoperoxide Synthases / metabolism Rosiglitazone Stomach Neoplasms / drug therapy Stomach Neoplasms / genetics Stomach Neoplasms / pathology* Thiazolidinediones / pharmacology Thiazolidinediones / therapeutic use Transcription Factors / agonists Transcription Factors / physiology* Tumor Cells, Cultured / drug effects
IF 17.943
Times Cited 63
Human and Animal Cells