title: NC2213: a novel methionine aminopeptidase 2 inhibitor in human colon cancer HT29 cells.
abstract: Methionine aminopeptidase 2 (MetAP2) is a bifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. MetAP2 is overexpressed in human colon cancer. In this report we screened various MetAP2 inhibitors and treated HT29 cells with various concentrations of compounds. We evaluated the expression of MetAP2 and pp60c-src expressions in HT29 cells. In addition we also carried out the cell proliferation and cell cycle analysis in the MetAP2 inhibitor-treated HT29 cells. The cell cycle analysis of HT29 treated with 1.0 microM of NC2213 showed an arrest in the G2 phase followed by an induction in the percentage of cells undergoing apoptosis in the sub-G1 phase. Western blot analysis revealed that the MetAP2 expression was dose-dependently decreased when the HT29 cells were treated with the 3,5-bis(benzylidene)-4-piperidone derivative (NC2213). In addition, phosphorylation of Src, a myristoylated oncoprotein was significantly decreased by 1.0 microM of NC2213 as revealed by Western blot analysis. Furthermore, NC2213 also inhibits the expression of pp60c-src in HT29 cells. Interestingly, this compound also inhibits the phosphorylation at Tyr416 of pp60c-src while increasing the phosphorylation at Tyr527 of pp60c-src. NC2213 inhibits the growth of HT29 cells by inducing apoptosis and might be useful for the treatment of human colon cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N4H4, Canada. ponniah.selvakumar@saskcancer.ca
authors.forename: Ponniah
authors.initials: P
authors.lastname: Selvakumar
authors.forename: Ashakumary
authors.initials: A
authors.lastname: Lakshmikuttyamma
authors.forename: Umashankar
authors.initials: U
authors.lastname: Das
authors.forename: Hari N
authors.initials: HN
authors.lastname: Pati
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Sharma
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D063208:Methionyl Aminopeptidases; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C547078:2-(3-(3,5-bis(4-nitrobenzylidene)-4-oxopiperidin-1-yl)-3-oxopropylsulfanyl)ethanesulfonic acid; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D010881:Piperidones; D013451:Sulfonic Acids; D016392:Proto-Oncogene Proteins pp60(c-src); D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases
references.citation: Nature. 1970 Aug 15;227(5259):672-6
references.pmid: 5432061
references.citation: Clin Cancer Res. 2005 Apr 1;11(7):2680-5
references.pmid: 15814649
references.citation: Biochim Biophys Acta. 2006 Apr;1765(2):148-54
references.pmid: 16386852
references.citation: Prog Lipid Res. 2007 Jan;46(1):1-36
references.pmid: 16846646
references.citation: Anticancer Res. 1997 Jul-Aug;17(4A):2571-6
references.pmid: 9252682
references.citation: Expert Opin Investig Drugs. 2000 Jun;9(6):1383-96
references.pmid: 11060750
references.citation: J Nippon Med Sch. 2004 Jun;71(3):172-80
references.pmid: 15226608
references.citation: Eur J Med Chem. 2008 Jan;43(1):1-7
references.pmid: 17499885
references.citation: Cancer. 2000 May 1;88(9):1992-9
references.pmid: 10813869
references.citation: Clin Cancer Res. 1997 Sep;3(9):1501-5
references.pmid: 9815836
references.citation: Clin Cancer Res. 2004 Apr 15;10(8):2771-5
references.pmid: 15102683
references.citation: Nature. 1970 Aug 15;227(5259):680-5
references.pmid: 5432063
references.citation: Cancer Res. 1994 Jul 1;54(13):3407-12
references.pmid: 8012959
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Bioorg Med Chem. 2004 Jul 15;12(14):3871-83
references.pmid: 15210154
references.citation: Biochem Biophys Res Commun. 2004 Sep 24;322(3):1012-7
references.pmid: 15336565
references.citation: Am J Pathol. 2001 Aug;159(2):721-31
references.pmid: 11485930
references.citation: Br J Cancer. 1994 Feb;69(2):212-6
references.pmid: 8297716
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15183-8
references.pmid: 9860943
references.citation: Exp Cell Res. 1999 Feb 1;246(2):376-83
references.pmid: 9925753
references.citation: J Cell Biochem. 2000 Apr;77(3):465-73
references.pmid: 10760954
references.citation: Oncogene. 2008 Jun 26;27(28):3967-76
references.pmid: 18264137
references.citation: Cancer Res. 1994 Apr 15;54(8):2073-6
references.pmid: 7513609
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12782-7
references.pmid: 11070090
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6427-32
references.pmid: 10841547
references.citation: Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350-4
references.pmid: 388439
references.citation: J Clin Oncol. 1998 Apr;16(4):1444-9
references.pmid: 9552050
references.citation: Cancer Res. 2003 Aug 1;63(15):4368-74
references.pmid: 12907606
references.citation: Lab Invest. 2002 Jul;82(7):893-901
references.pmid: 12118091
references.citation: Oncology. 2003;65(1):37-45
references.pmid: 12837981
references.citation: Cancer Res. 1987 Feb 15;47(4):936-42
references.pmid: 3802100
references.citation: Oncogene. 2008 Jun 19;27(27):3831-44
references.pmid: 18246120
references.citation: J Mol Biol. 1999 Jul 16;290(3):607-14
references.pmid: 10395817
references.citation: Chem Biol. 2007 Jul;14(7):764-74
references.pmid: 17656313
references.citation: Carcinogenesis. 2003 Mar;24(3):443-51
references.pmid: 12663503
references.citation: World J Gastroenterol. 2005 Feb 14;11(6):771-7
references.pmid: 15682466
references.citation: Biochemistry. 2003 May 13;42(18):5453-60
references.pmid: 12731887