Carcinogenesis Advance Access originally published online on July 15, 2004
Carcinogenesis 2004 25(11):2191-2199; doi:10.1093/carcin/bgh234
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Carcinogenesis vol.25 no.11 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Suppressed NF-
B and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF-
-induced apoptosis in human cancer cells
1 Department of Community, Occupational and Family Medicine, Faculty of Medicine (MD3), National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore, 2 School of Public Health, Sun Yat-sen University, Guangzhou 510089, People's Republic of China and 3 Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
4 To whom correspondence should be addressed Email: cofshm{at}nus.edu.sg
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-
B (NF-B) 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)-
-induced apoptosis in human cancer cells. Pre-treatment with PN greatly sensitized various human cancer cells to TNF--induced apoptosis. Such sensitization is closely associated with the inhibitory effect of PN on TNF--mediated NF-B activation. Our study revealed a new mechanism that PN inhibits TNF--mediated NF-B 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--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--induced apoptosis. It is thus believed that suppressed NF-B activation and sustained JNK activation contribute to the sensitization effect of PN to TNF--mediated cell death in human cancer cells.
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