Suppressed NF-kB and Sustained JNK Activation Contribute to the Sensitization Effect of Parthenolide to TNF-A Induced Apoptosis in Human Cancer Cells

Details

• Personal Author:
  Lin ZN ; Ong CN ; Shen HM ; Shi X ; Yang CF ; Zhang S
• Description:
  Parthenolide (PN) is the main sesquiterpene lactone found in feverfew with potent anti-inflammatory function. The anticancer property of PN has been demonstrated in both in vitro cell culture and in vivo animal model, while the molecular mechanisms remain to be further elucidated. In the present study, we evaluated the involvement of nuclear transcription factor-kB (NF-kB) and c-Jun N-terminal kinase (JNK) in the anticancer activity of PN by examining the sensitization effect of PN on tumor necrosis factor (TNF)-a-induced apoptosis in human cancer cells. Pre-treatment with PN greatly sensitized various human cancer cells to TNF-a-induced apoptosis. Such sensitization is closely associated with the inhibitory effect of PN on TNF-a-mediated NF-kB activation. Our study revealed a new mechanism that PN inhibits TNF-a-mediated NF-kB activation via disrupting the recruitment of the IB kinases (IKK) complex to TNF receptor, which then blocked the subsequent signaling events including IKK kinase activation, IB degradation, p65 nuclear translocation, DNA binding and transactivation. Moreover, PN also markedly enhanced and sustained TNF-a-mediated JNK activation. A specific JNK inhibitor (SP600125), as well as over-expression of dominant-negative forms of JNK1 and JNK2 abolished the sensitization effect of PN on TNF-a-induced apoptosis. It is thus believed that suppressed NF-kB activation and sustained JNK activation contribute to the sensitization effect of PN to TNF-a-mediated cell death in human cancer cells. [Description provided by NIOSH]
• Subjects:
  Animals Cells, Cultured Hypersensitivity Laboratories Neoplasms Occupational Health Safety
• Keywords:
  Animal-studies Cancer Cell-cultures Cell-damage In-vitro-studies In-vivo-studies Laboratory-animals Models Sensitization
• ISSN:
  0143-3334
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  25
• Issue:
  11
• NIOSHTIC Number:
  nn:20025979
• Citation:
  Carcinogenesis 2004 Nov; 25(11):2191-2199
• Contact Point Address:
  Department of Community, Occupational and Family Medicine, Faculty of Medicine (MD3), National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore
• Email:
  cofshm@nus.edu.sg
• Federal Fiscal Year:
  2005
• Peer Reviewed:
  True
• Source Full Name:
  Carcinogenesis
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7e8fdb6f679e8a18abccf7d525c5efa3bc1ae8e85678bcc82f78c28fc39ab00c6cd9e8e4dc6579b80181885f1ade9a5cb00d86409531855c00e9f7cd60876d6c
• Download URL:
  https://stacks.cdc.gov/view/cdc/197130/cdc_197130_DS1.pdf
• File Type:
  [PDF - 562.82 KB ]