Journal article
IκB Kinase Activation Is Involved in Regulation of Paclitaxel-Induced Apoptosis in Human Tumor Cell Lines
Molecular pharmacology, Vol.61(1), pp.105-113
01/01/2002
DOI: 10.1124/mol.61.1.105
PMID: 11752211
Abstract
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 prodeins, 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.
Details
- Title: Subtitle
- IκB Kinase Activation Is Involved in Regulation of Paclitaxel-Induced Apoptosis in Human Tumor Cell Lines
- Creators
- Yi Huang - Medical University of South CarolinaWeimin Fan - Medical University of South Carolina
- Resource Type
- Journal article
- Publication Details
- Molecular pharmacology, Vol.61(1), pp.105-113
- DOI
- 10.1124/mol.61.1.105
- PMID
- 11752211
- ISSN
- 0026-895X
- eISSN
- 1521-0111
- Language
- English
- Date published
- 01/01/2002
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383903102771
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