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Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin

Oncogene volume 20, pages 859–868 (2001)Cite this article

A Corrigendum to this article was published on 18 April 2002

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Abstract

The transcription factor NF-κB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that differ in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 μM) and doxorubicin (0.3 μM): Highly sensitive BxPC-3 and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistant to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-κB activity in all cell lines, whereas basal NF-κB binding was nearly undetectable in BxPc-3 and PT45-P1 cells, but rather high in Capan-1 and A818-4 cells, as demonstrated by gel-shift and luciferase assays. Treatment with various NF-κB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IκBα super-repressor, strongly enhanced the apoptotic effects of VP16 or doxorubicin on resistant Capan-1 and 818-4 cells. Our results indicate that under certain conditions the resistance of pancreatic carcinoma cells to chemotherapy is due to their constitutive NF-κB activity rather than the transient induction of NF-κB by some anti-cancer drugs. Blockade of basal NF-κB activity by well established drugs efficiently reduces chemoresistance of pancreatic cancer cells and offers the potential for improved therapeutic strategies.

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Abbreviations

FITC:

fluorescein isothiocyanate

IKK:

IκB kinase

NF-κB:

nuclear factor κB

PVDF:

polyvinylidene difluoride

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Acknowledgements

This work was supported by grants of the IZKF Kiel and the Hensel-Foundation.

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Author notes

  1. Jens Vorndamm: This work is part of a PhD thesis

Authors and Affiliations

  1. 1st Department of Medicine, Laboratory of Molecular Gastroenterology, University of Kiel, Germany

    Alexander Arlt, Jens Vorndamm, Maike Breitenbroich, Ulrich R Fölsch & Heiner Schäfer

  2. Department of General Surgery, Research Unit Molecular Oncology, University of Kiel, Germany

    Holger Kalthoff

  3. Department of Medicine I, St. Josef Hospital, Ruhr-University of Bochum, Germany

    Wolfgang E Schmidt

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  1. Alexander Arlt
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Arlt, A., Vorndamm, J., Breitenbroich, M. et al. Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene 20, 859–868 (2001). https://doi.org/10.1038/sj.onc.1204168

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