Suppressed NF- B and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF- -induced apoptosis in human cancer cells
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
... of PN on tumor necrosis factor (TNF)-a-induced apoptosis in human cancer cells. Pretreatment 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-amediated NF-kB activation. Our study revealed a new mechanism that PN inhibits TNF-a-mediated NF-kB activation via disrupting the recruitment of the IkB kinases (IKK) complex to TNF receptor, which then blocked the subsequent signaling events including IKK kinase activation, IkBa 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 overexpression of dominant-negative forms of JNK1 and JNK2 abolished the sensitization effect of PN on TNF-ainduced 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.