Nuclear Factor-κB/IκB Signaling Pathway May Contribute to the Mediation of Paclitaxel-induced Apoptosis in Solid Tumor Cells

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston 29425, USA.
Cancer Research (Impact Factor: 9.33). 09/2000; 60(16):4426-32.
Source: PubMed


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 IkappaB-alpha, the cytoplasmic inhibitor of transcription factor nuclear factor-kappaB (NF-kappaB), which in turn promoted the nuclear translocation of NF-kappaB and its DNA binding activity. In contrast, we found that glucocorticoids could antagonize paclitaxel-mediated NF-kappaB nuclear translocation and activation through induction of IkappaB-alpha protein synthesis. Northern blotting analyses demonstrated that the steady-state level of IkappaB-alpha mRNA was not affected by paclitaxel, which suggests that the down-regulation of IkappaB-alpha 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 IkappaB-alpha expression vectors remarkably increased their sensitivity to paclitaxel-induced apoptosis. Finally, we found that a key subunit of IkappaB kinase (IKK) complex, IKKbeta, was up-regulated by paclitaxel, which implies that paclitaxel might down-regulate IkappaB-alpha through modulation of IKKbeta activity. All of these results suggest that the NF-kappaB/IkappaB-alpha signaling pathway may contribute to the mediation of paclitaxel-induced cell death in solid tumor cells.

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Available from: Weimin Fan, Dec 27, 2013
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    • "In this context, IκBα degradation and NF-κB activation has been shown to precede cell death in cisplatin treated human head and neck squamous cell carcinoma cells [29]. Moreover, Paclitaxel/Taxol, a naturally occurring antimitotic agent, was shown to induce apoptotic cell death in two cancer cell lines via a pathway independent of mitotic arrest [30]. Authors showed that short exposures to paclitaxel could activate or regulate multiple components of the NF-κB/IκB pathway, which in turn promoted the nuclear translocation of NF-κB and its DNA binding activity. "
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    • "It is well known that NF-κB has bidirectional modulatory effects on cell apoptosis [32,33]. Consistent with our findings, several studies showed that up-regulation of NF-κB was associated with cyanide-induced apoptosis [34], thymocyte apoptosis [35], both paclitaxel- and doxorubicin-induced apoptosis [36,37], and acted as anti-oncogene [38,39]. However, there were a few reports indicating that down-regulation of NF-κB signaling was observed in fenofibrate-related apoptosis in lung cancer [15] and mantle cell lymphoma [8]. "
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