Cell cycle inhibition by the anti-angiogenic agent TNP-470 is mediated by p53 and p21 <sup>WAF1/CIP1</sup>

DOI Web Site 被引用文献7件
  • Yi Zhang
    Center for Cancer Research, and Departments of Biology and Chemistry, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139
  • Eric C. Griffith
    Center for Cancer Research, and Departments of Biology and Chemistry, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139
  • Julien Sage
    Center for Cancer Research, and Departments of Biology and Chemistry, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139
  • Tyler Jacks
    Center for Cancer Research, and Departments of Biology and Chemistry, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139
  • Jun O. Liu
    Center for Cancer Research, and Departments of Biology and Chemistry, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139

抄録

<jats:p> Angiogenesis has been demonstrated to be essential for tumor growth and metastasis, and inhibition of angiogenesis is emerging as a promising strategy for treating cancer. Among the most potent inhibitors of angiogenesis is the fumagillin family of natural products. An analog of fumagillin, known as TNP-470 or AGM-1470, has been undergoing clinical trials for treating a variety of cancers. TNP-470 has been shown to block endothelial cell cycle progression in the late G <jats:sub>1</jats:sub> phase. Although the direct molecular target for TNP-470 has been identified as the type 2 methionine aminopeptidase (MetAP2), how inhibition of this enzyme leads to cell cycle arrest has remained unclear. We report that treatment of endothelial and other drug-sensitive cell types leads to the activation of the p53 pathway, causing an accumulation of the G <jats:sub>1</jats:sub> cyclin-dependent kinase inhibitor p21 <jats:sup>WAF1/CIP1</jats:sup> . The requirement of p53 and p21 <jats:sup>WAF1/CIP1</jats:sup> for the cell cycle inhibition by TNP-470 is underscored by the observation that cells deficient in p53 and p21 <jats:sup>WAF1/CIP1</jats:sup> are resistant to TNP-470. These results shed significant light on the mechanism of cell cycle inhibition by TNP-470 and suggest an alternative method of activating p53 in endothelial cells to halt angiogenesis and tumor progression. </jats:p>

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