Faculty Collaboration Database

The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene 2002 Sep 19;21(42):6510-9

Date

09/13/2002

Pubmed ID

12226754

DOI

10.1038/sj.onc.1205848

Scopus ID

2-s2.0-18644367630 (requires institutional sign-in at Scopus site)   161 Citations

Abstract

The Rel/NF-kappaB transcription factors play a key role in the regulation of apoptosis and in tumorigenesis by controlling the expressions of specific genes. To determine the role of the constitutive activity of RelA in tumorigenesis, we generated pancreatic tumor cell lines that express a dominant negative mutant of IkappaBalpha (IkappaBalphaM). In this report, we show that the inhibition of constitutive NF-kappaB activity, either by ectopic expression of IkappaBalphaM or by treating the cells with a proteasome inhibitor PS-341 which blocks intracellular degradation of IkappaBalpha proteins, downregulates the expression of bcl-xl. We identified two putative NF-kappaB binding sites (kappaB/A and B) in the bcl-xl promoter and found that these two sites interact with different NF-kappaB proteins. p65/p50 heterodimer interacts with kappaB/A site whereas p50/p50 homodimer interacts with kappaB/B. The bcl-xl promoter reporter gene assays reveal that NF-kappaB dependent transcriptional activation is mainly mediated by kappaB/A site, indicating that bcl-xl is one of the downstream target genes regulated by RelA/p50. Both IkappaBalphaM and PS-341 completely abolish NF-kappaB DNA binding activity; however, PS-341, but not ectopic expression of IkappaBalphaM, sensitized cells to apoptosis induced by Taxol. This is due to the Taxol-mediated reactivation of RelA through phosphorylation and degradation of IkappaBbeta and the re-expression of NF-kappaB regulated bcl-xl gene in these cancer cells as ectopic expression of the bcl-xl gene confers resistance to Taxol-induced apoptosis in PS-341 sensitized cells. These results demonstrate the important function of various NF-kappaB/IkappaB complexes in regulating anti-apoptotic genes in response to apoptotic stimuli, and they raise the possibility that NF-kappaB : IkappaBalpha and NF-kappaB : IkappaBbeta complexes are regulated by different upstream activators, and that NF-kappaB plays a key role in pancreatic tumorigenesis.

Author List

Dong QG, Sclabas GM, Fujioka S, Schmidt C, Peng B, Wu T, Tsao MS, Evans DB, Abbruzzese JL, McDonnell TJ, Chiao PJ

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Apoptosis
Boronic Acids
Bortezomib
Cell Differentiation
Cell Division
Chloramphenicol O-Acetyltransferase
DNA-Binding Proteins
Drug Resistance, Neoplasm
Gene Expression Regulation
HeLa Cells
Humans
I-kappa B Proteins
NF-kappa B
Paclitaxel
Pancreatic Neoplasms
Promoter Regions, Genetic
Protease Inhibitors
Proto-Oncogene Proteins c-bcl-2
Pyrazines
Pyrophosphatases
Transcriptional Activation
Tumor Cells, Cultured
Up-Regulation
bcl-X Protein