title: PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells.
abstract: Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.
authors.affiliation: Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea.
authors.forename: M S
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea.
authors.forename: M K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju, Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju, Korea.
authors.forename: H K
authors.initials: HK
authors.lastname: Yi
authors.affiliation: Department of Alternative Therapy, Jeonju University, Jeonju, Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Nam
authors.affiliation: Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea.
authors.forename: D Y
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea.
authors.forename: P H
authors.initials: PH
authors.lastname: Hwang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D047495:PPAR gamma