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-κB (NF-κB) 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)-α-induced apoptosis in human cancer cells. Pre-treatment with PN greatly sensitized various human cancer cells to TNF-α-induced apoptosis. Such sensitization is closely associated with the inhibitory effect of PN on TNF-α -mediated NF-κB activation. Our study revealed a new mechanism that PN inhibits TNF-α-mediated NF-κB activation via disrupting the recruitment of the IκB kinases (IKK) complex to TNF receptor, which then blocked the subsequent signaling events including IKK kinase activation, IκBα degradation, p65 nuclear translocation, DNA binding and transactivation. Moreover, PN also markedly enhanced and sustained TNF-α-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-α -induced apoptosis. It is thus believed that suppressed NF-κB activation and sustained JNK activation contribute to the sensitization effect of PN to TNF-α-mediated cell death in human cancer cells.
|Number of pages||9|
|State||Published - Nov 2004|
Bibliographical noteFunding Information:
This work was supported by a research grant from the National Medical Research Council (NMRC/0465/2000), Singapore and an Academic Research Grant by the National University of Singapore (R-186-000-050-112). S.Z. is supported by a NUS scholarship and Z.L. is supported by a fellowship from the China Medical Board (CMB), New York, USA. The authors would like to thank Dr A.G.Porter for kindly providing DN-JNK1/DN-JNK2 constructs and Dr Z.G.Liu for the CrmA expression vector.
ASJC Scopus subject areas
- Cancer Research