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Vol. 61, Issue 1, 105-113, January 2002

Ikappa B Kinase Activation Is Involved in Regulation of Paclitaxel-Induced Apoptosis in Human Tumor Cell Lines

Yi Huang and Weimin Fan

Departments of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina

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 kappa Balpha (Ikappa Balpha ) degradation and nuclear factor-kappa B (NF-kappa B) activation might contribute to the mediation of paclitaxel-induced apoptosis. In this study, using a novel Ikappa Balpha phosphorylation inhibitor, we demonstrated that the blockage of paclitaxel-induced Ikappa Balpha 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 Ikappa B kinase (IKK), which is responsible for the phosphorylation and degradation of Ikappa B proteins, was significantly activated by paclitaxel in these paclitaxel-sensitive tumor cells. Stable transfection of a mutant Ikappa Balpha 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-kappa B activation that subsequently mediates paclitaxel-induced apoptotic cell death in solid tumor cells.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics