PT - JOURNAL ARTICLE AU - Yi Huang AU - Weimin Fan TI - IκB Kinase Activation Is Involved in Regulation of Paclitaxel-Induced Apoptosis in Human Tumor Cell Lines AID - 10.1124/mol.61.1.105 DP - 2002 Jan 01 TA - Molecular Pharmacology PG - 105--113 VI - 61 IP - 1 4099 - http://molpharm.aspetjournals.org/content/61/1/105.short 4100 - http://molpharm.aspetjournals.org/content/61/1/105.full SO - Mol Pharmacol2002 Jan 01; 61 AB - 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 κBα (IκBα) degradation and nuclear factor-κB (NF-κB) activation might contribute to the mediation of paclitaxel-induced apoptosis. In this study, using a novel IκBα phosphorylation inhibitor, we demonstrated that the blockage of paclitaxel-induced IκBα 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 IκB kinase (IKK), which is responsible for the phosphorylation and degradation of IκB proteins, was significantly activated by paclitaxel in these paclitaxel-sensitive tumor cells. Stable transfection of a mutant IκBα lacking Ser32 and Ser36 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-κB activation that subsequently mediates paclitaxel-induced apoptotic cell death in solid tumor cells.