The function of multiple IκB:Nf-κB complexes in the resistance of cancer cells to Taxol-induced apoptosis

• Published in: Oncogene Vol. 21; no. 42; pp. 6510 - 6519
• Main Authors: DONG, Qiang G, SCLABAS, Guido M, CHIAO, Paul J, FUJIOKA, Shuichi, SCHMIDT, Christian, BAILU PENG, TIANAI WU, TSAO, Ming-Sound, EVANS, Douglas B, ABBRUZZESE, James L, MCDONNELL, Timothy J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 19-09-2002; Nature Publishing Group
• Subjects: Apoptosis; Bcl-x protein; Binding sites; Biological and medical sciences; Cancer cells; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Control; DNA binding proteins; Ectopic expression; Fundamental and applied biological sciences. Psychology; Gene expression; Genes; Genetic aspects; Health aspects; Molecular and cellular biology; NF-κB protein; Paclitaxel; Pancreas; Pancreatic cancer; Phosphorylation; Proteasome inhibitors; RelA protein; Reporter gene; Transcription activation; Transcription factors; Tumor cell lines; Tumorigenesis; United States; Human; Multicatalytic endopeptidase complex; bcl-x1; Enzyme; Taxol; Molecular interaction; Tumorigenicity; Malignant tumor; Gene expression; IκB; Peptidases; NF-κB; Cell line; Sensitivity resistance; Digestive diseases; Hydrolases; Transcription factor NFκB; Onc gene; Apoptosis; Pancreatic disease
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205848

The Rel/NF-κB 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 IκBα (IκBαM). In this report, we show that the inhibition of constitutive NF-κB activity, either by ectopic expression of IκBαM or by treating the cells with a proteasome inhibitor PS-341 which blocks intracellular degradation of IκBα proteins, downregulates the expression of bcl-xl. We identified two putative NF-κB binding sites (κB/A and B) in the bcl-xl promoter and found that these two sites interact with different NF-κB proteins. p65/p50 heterodimer interacts with κB/A site whereas p50/p50 homodimer interacts with κB/B. The bcl-xl promoter reporter gene assays reveal that NF-κB dependent transcriptional activation is mainly mediated by κB/A site, indicating that bcl-xl is one of the downstream target genes regulated by RelA/p50. Both IκBαM and PS-341 completely abolish NF-κB DNA binding activity; however, PS-341, but not ectopic expression of IκBαM, sensitized cells to apoptosis induced by Taxol. This is due to the Taxol-mediated reactivation of RelA through phosphorylation and degradation of IκBβ and the re-expression of NF-κB 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-κB/IκB complexes in regulating anti-apoptotic genes in response to apoptotic stimuli, and they raise the possibility that NF-κB : IκBα and NF-κB : IκBβ complexes are regulated by different upstream activators, and that NF-κB plays a key role in pancreatic tumorigenesis.