title: Functional characterization of peroxisome proliferator-activated receptor-β/δ expression in colon cancer.
abstract: This study critically examined the role of PPARβ/δ in colon cancer models. Expression of PPARβ/δ mRNA and protein was lower and expression of CYCLIN D1 protein higher in human colon adenocarcinomas compared to matched non-transformed tissue. Similar results were observed in colon tumors from Apc(+/Min-FCCC) mice compared to control tissue. Dietary administration of sulindac to Apc(+/Min-FCCC) mice had no influence on expression of PPARβ/δ in normal colon tissue or colon tumors. Cleaved poly (ADP-ribose) polymerase (PARP) was either increased or unchanged, while expression of 14-3-3ε was not influenced in human colon cancer cell lines cultured with the PPARβ/δ ligand GW0742 under conditions known to increase apoptosis. While DLD1 cells exhibited fewer early apoptotic cells after ligand activation of PPARβ/δ following treatment with hydrogen peroxide, this change was associated with an increase in late apoptotic/necrotic cells, but not an increase in viable cells. Stable over-expression of PPARβ/δ in human colon cancer cell lines enhanced ligand activation of PPARβ/δ and inhibition of clonogenicity in HT29 cells. These studies are the most quantitative to date to demonstrate that expression of PPARβ/δ is lower in human and Apc(+/Min-FCCC) mouse colon tumors than in corresponding normal tissue, consistent with the finding that increasing expression and activation of PPARβ/δ in human colon cancer cell lines inhibits clonogenicity. Because ligand-induced attenuation of early apoptosis can be associated with more late, apoptotic/necrotic cells, but not more viable cells, these studies illustrate why more comprehensive analysis of PPARβ/δ-dependent modulation of apoptosis is required in the future.
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Foreman
authors.forename: Wen-Chi L
authors.initials: WC
authors.lastname: Chang
authors.forename: Prajakta S
authors.initials: PS
authors.lastname: Palkar
authors.forename: Bokai
authors.initials: B
authors.lastname: Zhu
authors.forename: Michael G
authors.initials: MG
authors.lastname: Borland
authors.forename: Jennie L
authors.initials: JL
authors.lastname: Williams
authors.forename: Lance R
authors.initials: LR
authors.lastname: Kramer
authors.forename: Margie L
authors.initials: ML
authors.lastname: Clapper
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000235:genetics* / Q000378:metabolism; D048068:PPAR-beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047494:PPAR delta; D048068:PPAR-beta; D006861:Hydrogen Peroxide