NC2213: a novel methionine aminopeptidase 2 inhibitor in human colon cancer HT29 cells.
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.
Selvakumar
Ponniah
P
Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N4H4, Canada. ponniah.selvakumar@saskcancer.ca
Lakshmikuttyamma
Ashakumary
A
Das
Umashankar
U
Pati
Hari N
HN
Dimmock
Jonathan R
JR
Sharma
Rajendra K
RK
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*
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
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