Selective Induction of Apoptosis Through the FADD/Caspase-8 Pathway by a p53 C-Terminal Peptide in Human Pre-Malignant and Malignant Cells

Details

• Personal Author:
  Brandt-Rauf PW ; Dinnen RD ; Fine RL ; Li Y ; Mao Y ; Rosal RV ; Williams AC
• Description:
  A p53 C-terminal peptide (aa 361-382, p53p), fused at its C-terminus to the minimal carrier peptide of antennapedia (17 aa, Ant; p53p-Ant), induced rapid apoptosis in human cancer cells, via activation of the Fas pathway. We examined p53p-Ant mechanism of action, toxicity in various human normal, non-malignant, pre-malignant and malignant cancer cells and investigated its biophysical characteristics. p53p-Ant selectively induced cell death in only pre-malignant or malignant cells in a p53-dependent manner and was not toxic to normal and non-malignant cells. p53p-Ant was more toxic to the mutant p53 than wild-type p53 phenotype in H1299 lung cancer cells stably expressing human temperature-sensitive p53 mutant 143Ala. Surface plasmon resonance (BIACORE) analysis demonstrated that this peptide had higher binding affinity to mutant p53 as compared to wild-type p53. p53p-Ant induced-cell death had the classical morphological characteristics of apoptosis and had no features of necrosis. The mechanism of cell death by p53p-Ant was through the FADD/caspase-8-dependent pathway without the involvement of the TRAIL pathway, Bcl-2 family and cell cycle changes. Blocking Fas with antibody did not alter the peptide's effect, suggesting that Fas itself did not interact with the peptide. Transfection with a dominant-negative FADD with a deleted N-terminus inhibited p53p-Ant-induced apoptosis. Its mechanism of action is related to the FADD-induced pathway without restoration of other p53 functions. p53p-Ant is a novel anticancer agent with unique selectivity for human cancer cells and could be useful as a prototype for the development of new anti-cancer agents. [Description provided by NIOSH]
• Subjects:
  Hazardous Substances Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Biophysics Cancer Cell-damage Humans Lung-cancer Pulmonary-system-disorders Respiratory-system-disorders Toxic-effects Toxins
• ISSN:
  0020-7136
• 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
• Pages in Document:
  55-64
• Volume:
  115
• Issue:
  1
• NIOSHTIC Number:
  nn:20028853
• Citation:
  Int J Cancer 2005 May; 115(1):55-64
• Contact Point Address:
  Robert L. Fine, College of Physicians and Surgeons, Columbia University Medical Center, 650 West 168th Street, BB 20-05, New York, NY 10032
• Email:
  rlf20@columbia.edu
• Federal Fiscal Year:
  2005
• 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:
  International Journal of Cancer
• End Date:
  20110630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:c4d2d78b8f9e531573b3827647942fef2f8c382cbd41e96e868bb8f3bbd9e1cefabb71001b5a924f8ca8066818406137926beea4754e90d54a00219676531762
• Download URL:
  https://stacks.cdc.gov/view/cdc/189954/cdc_189954_DS1.pdf
• File Type:
  [PDF - 512.21 KB ]