Selective Induction of Apoptosis in Mutant p53 Premalignant and Malignant Cancer Cells by PRIMA-1 Through the C-Jun-NH2-Kinase Pathway

Details

• Personal Author:
  Brandt-Rauf PW ; Fine RL ; Li Y ; Mao Y ; Williams AC
• Description:
  PRIMA-1 (p53 reactivation and induction of massive apoptosis) is a chemical compound that was originally identified as a selective mutant p53-dependent growth suppressor by screening a library of low-molecular-weight compounds. However, its mechanism of action is unknown. In this study, we examined toxicity of PRIMA-1 to three premalignant human colorectal adenoma cell lines (RG/C2, BR/C1, and AA/C1) and four colorectal carcinoma cell lines (DLD-1, SW480, LOVO, and HCT116) and its mechanism of action. It selectively induced apoptosis only in the mutant p53 premalignant and malignant colon cell lines, but was not toxic to the wild-type p53 premalignant and malignant colon cell lines. Using stable transfectants of temperature-sensitive p53 mutant Ala(143) in null p53 H1299 lung cancer cells, we found that PRIMA-1 induced significantly more apoptosis in cells with mutant p53 conformation (37 degrees C) than the wild-type p53 conformation (32.5 degrees C). Cell cycle analysis indicated that its inhibition of cell growth was correlated with induction of G(2) arrest. Western blot analysis showed PRIMA-1 increased p21 and GADD45 expression selectively in the mutant p53 cells. However, Fas, Bcl-2 family proteins, and caspases were not involved in PRIMA-1-induced cell death. The c-Jun-NH(2)-kinase (JNK) inhibitor SP 600125, but not p38 mitogen-activated protein kinase inhibitor SB 203580 or extracellular signal-regulated kinase inhibitor PD 98059, blocked PRIMA-1-induced apoptosis. Transfection with a dominant-negative phosphorylation mutant JNK, but not a dominant-negative p38 or wild-type JNK, inhibited PRIMA-1-induced cell death, suggesting that the JNK pathway plays an important role in PRIMA-1-induced apoptosis. PRIMA-1 is a highly selective small molecule toxic to p53 mutant cells and may serve as a prototype for the development of new p53-targeting agents for therapy of premalignant and malignant cells. [Description provided by NIOSH]
• Subjects:
  Cells, Cultured Hazardous Substances Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Cancer Cell-cultures Cell-growth Lung-cancer Pulmonary-system-disorders Respiratory-system-disorders Toxic-effects
• ISSN:
  1535-7163
• 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:
  4
• Issue:
  6
• NIOSHTIC Number:
  nn:20028851
• Citation:
  Mol Cancer Ther 2005 Jun; 4(6):901-909
• Contact Point Address:
  Robert L. Fine, Division of Medical Oncology, College of Physicians and Surgeons, Columbia University Medical Center, Black Building 20-25, 650 West 168th Street, 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:
  Molecular Cancer Therapeutics
• End Date:
  20110630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:0024b12d080af62cb518e9ecc079bc81cbcbd65196235e26c66ecf688c7e18911498fc46446bbb933a0b426aee1240ffdc91455d497fa9613f642c90ba3535da
• Download URL:
  https://stacks.cdc.gov/view/cdc/189953/cdc_189953_DS1.pdf
• File Type:
  [PDF - 866.27 KB ]