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 μM 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 μM 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.
Highlights
Various reports suggested that Methionine aminopeptidase 2 (MetAP2) plays an important role in the growth of different types of tumors [5]
We demonstrated the high expression of MetAP2 in colorectal adenocarcinoma patients [12]
We identified 2-{3-[3,5-bis[4nitrobenzylidene]-4-oxopiperidin-1-yl]-3-oxopropylsulfanyl} ethanesulfonic acid NC2213 (Figure 1), which is structurally divergent from fumagillin, as an inhibitor of MetAP2
Summary
HT29 colon cancer cells were treated with NC2213 at a concentration range of 0 to 5.0 μM for 96 hours to confirm a dosedependent inhibitory effect. To investigate the inhibition of MetAP2 by NC2213, the dose-dependent effects of NC2213 were evaluated by Western blot analysis. HT29 cells, treated with NC2213 for 48 hours, led to a dramatic decrease in MetAP2 expression (Figure 3A). Inhibition of MetAP2 by TNP470 has been shown to activate p53 for cell-cycle arrest [25,26].
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