title: Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in ApcMin/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways.
abstract: A large body of studies has suggested that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, such as thiazolidinedione, are potent candidates for chemopreventive agents. MCC-555 is a PPARgamma/alpha dual agonist and has been shown previously to induce apoptosis in vitro; however, the molecular mechanisms by which MCC-555 affects antitumorigenesis in vivo are poorly understood. In this study, we explored the antitumorigenic effects of MCC-555 both in cell culture and in Apc-deficient mice, an animal model for human familial adenomatous polyposis. MCC-555 increased MUC2 expression in colorectal and lung cancer cells, and treatment with the PPARgamma antagonist GW9662 revealed that MUC2 induction by MCC-555 was mediated in a PPARgamma-dependent manner. Moreover, MCC-555 increased transcriptional activity of human and mouse MUC2 promoters. Subsequently, treatment with MCC-555 (30 mg/kg/d) for 4 weeks reduced the number of small intestinal polyps to 54.8% of that in control mice. In agreement with in vitro studies, enhanced Muc2 expression was observed in the small intestinal tumors of Min mice treated with MCC-555, suggesting that MUC2 expression may be associated at least in part with the antitumorigenic action of MCC-555. In addition, highly phosphorylated extracellular signal-regulated kinase (ERK) was found in the intestinal tumors of MCC-555-treated Min mice, and inhibition of the ERK pathway by a specific inhibitor markedly suppressed MCC-555-induced Muc2 expression in vitro. Overall, these results indicate that MCC-555 has a potent tumor suppressor activity in intestinal tumorigenesis, likely involving MUC2 up-regulation by ERK and PPARgamma pathways.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Maria
authors.initials: M
authors.lastname: Cekanova
authors.forename: Michael F
authors.initials: MF
authors.lastname: McEntee
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Renes
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency*; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007417:Intestinal Polyps / Q000201:enzymology* / Q000473:pathology*; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D055262:Mucin-2; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D008024:Ligands; C524625:MUC2 protein, human; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D045162:Thiazolidinediones; D048049:Extracellular Signal-Regulated MAP Kinases; C115174:netoglitazone
references.citation: Mol Pharmacol. 2005 Dec;68(6):1782-92
references.pmid: 16155208
references.citation: Cancer Res. 1997 Oct 1;57(19):4267-73
references.pmid: 9331087
references.citation: J Investig Med. 2001 Sep;49(5):413-20
references.pmid: 11523697
references.citation: Oncogene. 2007 Oct 4;26(45):6566-76
references.pmid: 17471237
references.citation: Jpn J Cancer Res. 1999 Jan;90(1):75-80
references.pmid: 10076568
references.citation: Biochem Biophys Res Commun. 2004 Dec 17;325(3):952-60
references.pmid: 15541382
references.citation: Gastroenterology. 2003 Feb;124(2):361-7
references.pmid: 12557142
references.citation: Mol Cancer Ther. 2006 May;5(5):1362-70
references.pmid: 16731770
references.citation: Nat Med. 1998 Sep;4(9):1046-52
references.pmid: 9734398
references.citation: J Biol Chem. 2002 Sep 6;277(36):32624-31
references.pmid: 12077118
references.citation: Cancer Res. 2005 Feb 15;65(4):1561-9
references.pmid: 15735046
references.citation: Science. 2002 Mar 1;295(5560):1726-9
references.pmid: 11872843
references.citation: Cancer Res. 2003 Sep 15;63(18):6090-5
references.pmid: 14522940
references.citation: Exp Mol Med. 2005 Apr 30;37(2):101-10
references.pmid: 15886523
references.citation: Mol Cell. 1999 Jun;3(6):799-804
references.pmid: 10394368
references.citation: J Biol Chem. 1998 Dec 4;273(49):32679-84
references.pmid: 9830009
references.citation: Mol Cancer Ther. 2006 May;5(5):1352-61
references.pmid: 16731769
references.citation: Clin Cancer Res. 2004 Feb 15;10(4):1508-20
references.pmid: 14977855
references.citation: J Cell Biol. 2004 Jul 5;166(1):37-47
references.pmid: 15240568
references.citation: Mol Pharmacol. 2008 Mar;73(3):709-17
references.pmid: 18055759
references.citation: J Biol Chem. 2001 Aug 10;276(32):29681-7
references.pmid: 11397807
references.citation: N Engl J Med. 2004 Sep 9;351(11):1106-18
references.pmid: 15356308
references.citation: Cancer Metastasis Rev. 2004 Jan-Jun;23(1-2):77-99
references.pmid: 15000151
references.citation: Cancer Res. 2006 Feb 15;66(4):2376-84
references.pmid: 16489044
references.citation: Cell Signal. 2005 Jan;17(1):111-9
references.pmid: 15451031
references.citation: J Cell Physiol. 2006 Nov;209(2):428-38
references.pmid: 16883598
references.citation: Int J Biochem Cell Biol. 2000 Oct;32(10):1085-92
references.pmid: 11091141
references.citation: J Biol Chem. 2002 Aug 30;277(35):32258-67
references.pmid: 12077147
references.citation: Gut. 2007 Nov;56(11):1557-63
references.pmid: 17604322
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 May;68(5):323-30
references.pmid: 12711249
references.citation: Nat Med. 1998 Sep;4(9):1053-7
references.pmid: 9734399
references.citation: J Biol Chem. 2004 Feb 20;279(8):6883-92
references.pmid: 14662774
references.citation: J Histochem Cytochem. 1996 Oct;44(10):1161-6
references.pmid: 8813081
references.citation: Cancer Epidemiol Biomarkers Prev. 2003 May;12(5):391-400
references.pmid: 12750232
references.citation: J Clin Pathol. 1997 May;50(5):417-21
references.pmid: 9215126
references.citation: Gut. 2002 May;50(5):658-64
references.pmid: 11950812
references.citation: Oncogene. 2004 Jul 22;23(33):5594-606
references.pmid: 15184882
references.citation: Biochem Biophys Res Commun. 2006 Jul 21;346(1):83-8
references.pmid: 16759638
references.citation: Gastroenterology. 1998 Nov;115(5):1049-55
references.pmid: 9797355
references.citation: Cancer Res. 1992 Nov 1;52(21):5971-8
references.pmid: 1394223
references.citation: Carcinogenesis. 1999 Apr;20(4):635-40
references.pmid: 10223192
references.citation: J Pharmacol Exp Ther. 2006 Aug;318(2):863-71
references.pmid: 16682454
references.citation: J Biol Chem. 2002 Dec 13;277(50):48270-5
references.pmid: 12374798
references.citation: J Biol Chem. 2003 Feb 21;278(8):5845-53
references.pmid: 12475986
references.citation: Biochem Biophys Res Commun. 2000 Nov 30;278(3):704-11
references.pmid: 11095972
references.citation: Int J Oncol. 2008 Apr;32(4):809-19
references.pmid: 18360708
references.citation: Genes Cells. 2004 Nov;9(11):1113-23
references.pmid: 15507122
references.citation: Clin Cancer Res. 2003 Jan;9(1):1-9
references.pmid: 12538445
references.citation: J Biol Chem. 2003 Dec 19;278(51):51549-56
references.pmid: 14525978
references.citation: Drug Metab Pharmacokinet. 2006 Oct;21(5):347-56
references.pmid: 17072088