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Activation of targeted necrosis by a p53 peptide: a novel death pathway that circumvents apoptotic resistance.

Authors
Dinnen-RD; Drew-L; Petrylak-DP; Mao-Y; Cassai-N; Szmulewicz-J; Brandt-Rauf-P; Fine-RL
Source
J Biol Chem 2007 Sep; 282(37):26675-26686
NIOSHTIC No.
20032780
Abstract
Cancer cells escape apoptosis by intrinsic or acquired mechanisms of drug resistance. An alternative strategy to circumvent resistance to apoptosis could be through redirection into other death pathways, such as necrosis. However, necrosis is a nonspecific, nontargeted process resulting in cell lysis and inflammation of both cancer and normal cells and is therefore not a viable alternative. Here, we report that a C-terminal peptide of p53, called p53p-Ant, induced targeted necrosis only in multiple mutant p53 human prostate cancer lines and not normal cells, because the mechanism of cytotoxicity by p53p-Ant is dependent on the presence of high levels of mutant p53. Topotecan- and paclitaxel-resistant prostate cancer lines were as sensitive to p53p-Ant-induced targeted necrosis as parental lines. A massive loss of ATP pools and intracellular generation of reactive oxygen species was involved in the mechanism of targeted necrosis, which was inhibited by O(2)(.) scavengers. We hypothesize that targeted necrosis by p53p-Ant is dependent on mutant p53, is mediated by O(2)(.) loss and ATP, and can circumvent chemotherapy resistance to apoptosis. Targeted necrosis, as an alternative pathway for selective killing of cancer cells, may overcome the problems of nonspecificity in utilizing the necrotic pathway.
Keywords
Cell-damage; Cell-cultures; Blood-cells; Cancer; Cell-alteration; Cell-function; Cellular-reactions; Cellular-transport-mechanism; Chemotherapy
Contact
Experimental Therapeutics, Division of Medical Oncology, Columbia University, College of Physicians and Surgeons, 650 West 168th St., BB 20-05, New York, NY 10032
CODEN
JBCHA3
Publication Date
20070914
Document Type
Journal Article
Email Address
rlf20@columbia.edu
Funding Type
Grant
Fiscal Year
2007
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-007590
Issue of Publication
37
ISSN
0021-9258
Priority Area
Research Tools and Approaches: Cancer Research Methods
Source Name
Journal of Biological Chemistry
State
NY
Performing Organization
Columbia University Health Sciences
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