Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells

Y Huang; K R Johnson; J S Norris; W Fan

Back

Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells

Journal article

Peer reviewed

Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells

Y Huang, K R Johnson, J S Norris and W Fan

Cancer research (Chicago, Ill.), Vol.60(16), pp.4426-4432

08/15/2000

PMID: 10969788

View Online

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.

Antineoplastic Agents, Phytogenic - pharmacology

Apoptosis - drug effects

Apoptosis - physiology

DNA, Neoplasm - metabolism

DNA-Binding Proteins - biosynthesis

DNA-Binding Proteins - genetics

DNA-Binding Proteins - physiology

Gene Expression Regulation, Neoplastic - drug effects

Gene Expression Regulation, Neoplastic - physiology

Glucocorticoids - pharmacology

Humans

I-kappa B Kinase

I-kappa B Proteins - biosynthesis

I-kappa B Proteins - genetics

I-kappa B Proteins - physiology

NF-kappa B - antagonists & inhibitors

NF-kappa B - metabolism

NF-kappa B - physiology

NF-KappaB Inhibitor alpha

Oligodeoxyribonucleotides, Antisense - administration & dosage

Paclitaxel - pharmacology

Protein-Serine-Threonine Kinases - biosynthesis

Protein-Serine-Threonine Kinases - genetics

Signal Transduction - drug effects

Signal Transduction - physiology

Transfection

Translocation, Genetic - drug effects

Tumor Cells, Cultured

Up-Regulation - drug effects

Details

Title: Subtitle: Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells
Creators: Y Huang - Medical University of South Carolina
K R Johnson
J S Norris
W Fan
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.60(16), pp.4426-4432
PMID: 10969788
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: CA 82440 / NCI NIH HHS CA 71851 / NCI NIH HHS
Language: English
Date published: 08/15/2000
Academic Unit: Internal Medicine
Record Identifier: 9984383901902771

Metrics

3 Record Views

165 Times Cited - Web of Science