Activation of Targeted Necrosis by a p53 Peptide: A Novel Death Pathway That Circumvents Apoptotic Resistance

Details

• Personal Author:
  Brandt-Rauf P ; Cassai N ; Dinnen RD ; Drew L ; Fine RL ; Mao Y ; Petrylak DP ; Szmulewicz J
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Blood Cells, Cultured Neoplasms Occupational Health Safety
• Keywords:
  Blood-cells Cancer Cell-alteration Cell-cultures Cell-damage Cell-function Cellular-reactions Cellular-transport-mechanism Chemotherapy
• ISSN:
  0021-9258
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  282
• Issue:
  37
• NIOSHTIC Number:
  nn:20032780
• Citation:
  J Biol Chem 2007 Sep; 282(37):26675-26686
• Contact Point Address:
  Experimental Therapeutics, Division of Medical Oncology, Columbia University, College of Physicians and Surgeons, 650 West 168th St., BB 20-05, New York, NY 10032
• Email:
  rlf20@columbia.edu
• Federal Fiscal Year:
  2007
• NORA Priority Area:
  Research Tools and Approaches: Cancer Research Methods
• Performing Organization:
  Columbia University Health Sciences
• Peer Reviewed:
  True
• Start Date:
  20020601
• Source Full Name:
  Journal of Biological Chemistry
• End Date:
  20110630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:950aad6ce521ca9afd69ba309a7c06c0c32df8f563352f42a5712f172007d32b37aecde3b8b4c4826c82abc7d8bdfd941d1e4cb0c4f60c76a5c853c410eb338f
• Download URL:
  https://stacks.cdc.gov/view/cdc/186625/cdc_186625_DS1.pdf
• File Type:
  [PDF - 787.16 KB ]