Nuclear Factor-kappa B/I kappa B signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells

Paclitaxel (Taxol(R)), a naturally occurring antimitotic agent, has shown s ignificant cell-killing activity in a variety of tumor cells through induct ion of apoptosis. The mechanism by which paclitaxel induces cell death is n ot entirely clear, Recent studies in our Laboratory demonstrated that gluco corticoids selectively inhibited paclitaxel-induced apoptosis without affec ting the ability of paclitaxel to induce microtubule bundling and mitotic a rrest. This ending suggests that apoptotic cell death induced by paclitaxel may occur via a pathway independent of mitotic arrest, In the current stud y, through analyses of a number of apoptosis-associated genes or regulatory proteins, we discovered that paclitaxel significantly down-regulated I kap pa B-alpha, the cytoplasmic inhibitor of transcription factor nuclear facto r-kappa B (NF-kappa B), which in turn promoted the nuclear translocation of NF-kappa B and its DNA binding activity. In contrast, we found that glucoc orticoids could antagonize paclitaxel-mediated NF-kappa B nuclear transloca tion and activation through induction of I kappa B-alpha protein synthesis. Northern blotting analyses demonstrated that the steady-state level of I k appa B-alpha mRNA was not affected by paclitaxel, which suggests that the d own-regulation of I kappa B-alpha by paclitaxel is attributable to protein degradation rather than suppression of transcription, Furthermore, through transfection assays, we demonstrated that tumor cells stably transfected wi th antisense I kappa B-alpha expression vectors remarkably increased their sensitivity to paclitaxel-induced apoptosis, Finally, we found that a key s ubunit of I kappa B kinase (IKK) complex, IKK beta was up-regulated by pacl itaxel, which implies that paclitaxel might down-regulate I kappa B-alpha t hrough modulation of IKK beta activity. All of these results suggest that t he NF-kappa B/I kappa B-alpha signaling pathway may contribute to the media tion of paclitaxel-induced cell death in solid tumor cells.