IkappaB kinase activation is involved in regulation of paclitaxel-induced apoptosis in human tumor cell lines.
Paclitaxel (Taxol), a naturally occurring antimitotic agent, has shown significant cell-killing activity against human solid tumor cells through induction of apoptosis. The molecular mechanism underlying paclitaxel-induced apoptosis is not entirely clear. Using the unique inhibitory effect of glucocorticoids on paclitaxel-induced apoptosis, we recently discovered that paclitaxel-induced inhibitor kappaBalpha (IkappaBalpha) degradation and nuclear factor-kappaB (NF-kappaB) activation might contribute to the mediation of paclitaxel-induced apoptosis. In this study, using a novel IkappaBalpha phosphorylation inhibitor, we demonstrated that the blockage of paclitaxel-induced IkappaBalpha degradation inhibited apoptotic cell death in human breast cancer BCap37 and ovarian cancer OV2008 cell lines. Furthermore, in vitro kinase assays showed that the activity of IkappaB kinase (IKK), which is responsible for the phosphorylation and degradation of IkappaB proteins, was significantly activated by paclitaxel in these paclitaxel-sensitive tumor cells. Stable transfection of a mutant IkappaBalpha lacking Ser(32) and Ser(36) that was insensitive to IKK-mediated phosphorylation and degradation resulted in reduced sensitivity of tumor cells to paclitaxel-induced apoptosis. Moreover, we also found that the expression of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1, an upstream regulator of IKK, was up-regulated by paclitaxel. These findings suggest that the activation of IKK might play a critical role in the regulation of paclitaxel-induced NF-kappaB activation that subsequently mediates paclitaxel-induced apoptotic cell death in solid tumor cells.
Huang
Yi
Y
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Fan
Weimin
W
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D048728:MAP Kinase Kinase Kinase 1; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D000091402:Prohibitins; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012694:Serine / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000717331:PHB2 protein, human; D000091402:Prohibitins; D000072000:NF-KappaB Inhibitor alpha; D012694:Serine; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D017239:Paclitaxel