title: Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston 29425, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: K R
authors.initials: KR
authors.lastname: Johnson
authors.forename: J S
authors.initials: JS
authors.lastname: Norris
authors.forename: W
authors.initials: W
authors.lastname: Fan
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014178:Translocation, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D020319:Oligodeoxyribonucleotides, Antisense; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D017239:Paclitaxel