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- W3008049303 abstract "1519 Methionine aminopeptidase-2 (MetAP2) is a molecular target of TNP-470, an anti-angiogenic agent that has been evaluated in clinical trials as a cancer treatment. MetAP2 uniquely catalyzes the removal of the N-terminal methionine from a small number of nascent proteins whereas MetAP1 and other aminopeptidases carry out this methionine processing for the majority of cellular proteins. There are several lines of evidence that support MetAP2 as a promising cancer drug target. First, MetAP2 is over-expressed in tumors. Second, MetAP2 anti-sense oligonucleotides inhibit cell growth and induce apoptosis in tumor lines. Lastly, we have shown that a rationally designed reversible MetAP2 inhibitor, A-357300, recapitulates the anti-tumor activity of TNP-470 in murine cancer models. A-357300 selectively induced cytostasis by cell cycle arrest at the G1 phase in endothelial cells and in a subset of tumor cells such as HT-1080 human fibrosarcoma, but not in most primary cells of non-endothelial type. TNP-470 was reported to upregulate p53 and also to engage in the p53 pathway to exert p21 dependent G1 checkpoint control in endothelial cells. Here we report that the effect of A-357300 and TNP-470 on cell cycle and p53 in HT-1080 cells and normal human primary cells. MetAP2 inhibitors block the proliferation of HT-1080 cells. Thus, they provide an in vitro system for studying the molecular mechanism of cell cycle arrest by MetAP2 inhibitors. We treated HT-1080 cells with TNP-470 and A-357300 and determined the alteration of cell cycle proteins by Western Blot analysis. As a comparison, we also studied normal human primary cells. Our data showed that TNP-470 and A-357300 induced p53 and p21 in HT-1080 cells. Up-regulation of p53 protein by MetAP2 inhibitors was seen within 3 hours of drug exposure and occurred without serine phosphorylation of p53. In contrast, the DNA damaging agent etoposide induced p53 protein and its phosphorylation. To further understand the upregulation of p53, we performed QPCR to determine the mRNA expression. We observed that p53 mRNA was not affected, however, the level of p21 mRNA was increased. A-357300 and TNP-470 did not significantly alter the cell cycle of normal human mammary epithelial cells, bronchial epithelial cells, and smooth muscle cells. These MetAP2 inhibitors did not show significant induction of p53 and p21 in normal human primary cells. The data demonstrate that MetAP2 inhibitors activate the p53 pathway in HT-1080 tumors cells but not in normal cells." @default.
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- W3008049303 date "2004-04-01" @default.
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- W3008049303 title "MetAP2 inhibitors induce p53 in HT-1080 fibrosarcoma cells" @default.
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