Abstract
p53 mutations occur frequently in human tumors. The low-molecular-weight compound PRIMA-1MET reactivates mutant p53, induces apoptosis in human tumor cells and inhibits tumor xenograft growth in vivo. Here, we show that PRIMA-1MET induces mutant p53-dependent mitochondria-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-1MET treatment and causes a significant reduction in PRIMA-1MET-induced cell death. Our findings highlight a chain of cellular events triggered by PRIMA-1MET that lead to apoptotic cell death. This should facilitate further development and optimization of efficient PRIMA-1MET-based anticancer drugs.
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Abbreviations
- Δψm:
-
mitochondrial membrane potential
- FACS:
-
fluorescence-activated cell sorting
- G3PDH:
-
glyceraldehyde-3phosphate dehydrogenase
- PI:
-
propidium iodide
- fmk:
-
fluoromethyl ketone
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Acknowledgements
This study was supported by grants from the Swedish and Stockholm Cancer Societies, the Swedish Research Council, the EU 6th and 7th Framework Programs, and Karolinska Institutet. This publication reflects the author's views and not necessarily those of the EC partners. The information in this document is provided as is and no guarantee or warranty is given that the information is fit for any particular purpose. The user thereof uses the information at its sole risk and liability. The Community is not liable for any use that may be made of the information contained herein.
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Shen, J., Vakifahmetoglu, H., Stridh, H. et al. PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2. Oncogene 27, 6571–6580 (2008). https://doi.org/10.1038/onc.2008.249
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DOI: https://doi.org/10.1038/onc.2008.249
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