title: Activation of targeted necrosis by a p53 peptide: a novel death pathway that circumvents apoptotic resistance.
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.
authors.affiliation: Experimental Therapeutics Program, Division of Medical Oncology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Dinnen
authors.affiliation: Experimental Therapeutics Program, Division of Medical Oncology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
authors.forename: Lisa
authors.initials: L
authors.lastname: Drew
authors.affiliation: Experimental Therapeutics Program, Division of Medical Oncology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Petrylak
authors.affiliation: Experimental Therapeutics Program, Division of Medical Oncology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Pathology and Laboratory Medicine, Harbor Veterans Affairs Medical Center, SUNY Downstate Medical Center, Brooklyn, New York 11203.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cassai
authors.affiliation: Department of Pathology and Laboratory Medicine, Harbor Veterans Affairs Medical Center, SUNY Downstate Medical Center, Brooklyn, New York 11203.
authors.forename: Joseph
authors.initials: J
authors.lastname: Szmulewicz
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
authors.forename: Paul
authors.initials: P
authors.lastname: Brandt-Rauf
authors.affiliation: Experimental Therapeutics Program, Division of Medical Oncology, Columbia University, College of Physicians and Surgeons, New York, New York 10032. Electronic address: rlf20@columbia.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fine
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009154:Mutation; D009336:Necrosis; D010446:Peptide Fragments / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D020169:Caspases