PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2

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PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2

Authors
  • Jinfeng Shen
  • H Vakifahmetoglu
  • H Stridh
  • B Zhivotovsky
  • K G Wiman
Type
Published Article
Journal
Oncogene
Publisher
Springer Nature
Publication Date
Jul 11, 2008
Volume
27
Issue
51
Pages
6571–6580
Identifiers
DOI: 10.1038/onc.2008.249
Source
AIMS
Keywords
License
Green

Abstract

p53 mutations occur frequently in human tumors. The low-molecular-weight compound PRIMA-1 MET reactivates mutant p53, induces apoptosis in human tumor cells and inhibits tumor xenograft growth in vivo. Here, we show that PRIMA-1 MET induces mutant p53-dependent mito-chondria-mediated apoptosis through activation of caspase-2 with subsequent cytochrome c release and further activation of downstream caspase-9 and caspase-3. Inhibition of caspase-2 by a selective inhibitor and/or siRNA prevents cytochrome c release on PRIMA-1 MET treatment and causes a significant reduction in PRIMA-1 MET -induced cell death. Our findings highlight a chain of cellular events triggered by PRIMA-1 MET that lead to apoptotic cell death. This should facilitate further development and optimization of efficient PRIMA-1 MET -based anticancer drugs.

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