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Nuclear Factor-B/IB Signaling Pathway May Contribute to the Mediation of Paclitaxel-induced Apoptosis in Solid Tumor Cells¹

Departments of Pathology and Laboratory Medicine [Y. H., K. R. J., W. F.] and Microbiology and Immunology [J. S. N.], Medical University of South Carolina, Charleston, South Carolina 29425

Paclitaxel (Taxol^®), a naturally occurring antimitotic agent, has shown significant cell-killing activity in a variety of tumor cells through induction of apoptosis. The mechanism by which paclitaxel induces cell death is not entirely clear. Recent studies in our laboratory demonstrated that glucocorticoids selectively inhibited paclitaxel-induced apoptosis without affecting the ability of paclitaxel to induce microtubule bundling and mitotic arrest. This finding suggests that apoptotic cell death induced by paclitaxel may occur via a pathway independent of mitotic arrest. In the current study, through analyses of a number of apoptosis-associated genes or regulatory proteins, we discovered that paclitaxel significantly down-regulated IB-, the cytoplasmic inhibitor of transcription factor nuclear factor-B (NF-B), which in turn promoted the nuclear translocation of NF-B and its DNA binding activity. In contrast, we found that glucocorticoids could antagonize paclitaxel-mediated NF-B nuclear translocation and activation through induction of IB- protein synthesis. Northern blotting analyses demonstrated that the steady-state level of IB- mRNA was not affected by paclitaxel, which suggests that the down-regulation of IB- by paclitaxel is attributable to protein degradation rather than suppression of transcription. Furthermore, through transfection assays, we demonstrated that tumor cells stably transfected with antisense IB- expression vectors remarkably increased their sensitivity to paclitaxel-induced apoptosis. Finally, we found that a key subunit of IB kinase (IKK) complex, IKKß, was up-regulated by paclitaxel, which implies that paclitaxel might down-regulate IB- through modulation of IKKß activity. All of these results suggest that the NF-B/IB- signaling pathway may contribute to the mediation of paclitaxel-induced cell death in solid tumor cells.

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