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