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Role of NF-κB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death

Oncogene volume 22, pages 3243–3251 (2003)Cite this article

Abstract

Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gemcitabine appears to be the only clinically active drug but, because of pre-existing or acquired chemoresistance of most of the tumor cells, it failed to significantly improve the outcome of pancreatic carcinoma patients. The current study examined the relevance of nuclear factor κB (NF-κB) and PI3K/Akt in the resistance of five pancreatic carcinoma cell lines towards gemcitabine. Treatment for 24 h with gemcitabine (0.04–20 μ M) led to a strong induction of apoptosis in PT45-P1 and T3M4 cells but not in BxPc-3, Capan-1 and PancTu-1 cells. These resistant cell lines exhibited a high basal NF-κB activity in contrast to the sensitive cell lines. Furthermore, gemcitabine showed a dose-dependent induction of NF-κB. At a dose of 0.04 μ M, gemcitabine still induced apoptosis in the sensitive cell lines, but did not induce NF-κB. In addition, NF-κB inhibition by MG132, sulfasalazine or the IκBα super-repressor strongly diminished the resistance against gemcitabine (0.04–20 μ M). In contrast to this obvious correlation between basal NF-κB activity and gemcitabine resistance, PI3K/Akt seems not to be involved in gemcitabine resistance of these cell lines. Neither did the basal Akt activity correlate with the sensitivity towards gemcitabine treatment, nor did the inhibition of PI3K/Akt by LY294002 alter gemcitabine-induced apoptosis. These results indicate that constitutive NF-κB activity confers resistance against gemcitabine and that modulation of this activity by pharmacological or genetic approaches may have therapeutical potential when combined with gemcitabine in the treatment of pancreatic carcinoma.

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Abbreviations

NF-κB:

Nuclear factor κB

IκB:

inhibitor κB

IKK:

IκB kinase

FITC:

fluorescein isothiocyanate

PMSF:

phenyl methansulfonyl fluoride

P13K:

P13 Kinase

MDR:

multi drug resistance

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Acknowledgements

The excellent technical support by M Breitenbroich, F Grohmann and M Witt is greatly acknowledged. We thank Professor Holger Kalthoff, Molecular Oncology Research Group, Department of General Surgery, Kiel, for helpful discussions and providing PT45-P1 and PancTu1 cells. This work was supported by the German Research Society (DFG Scha 677/7-1) and the IZKF Kiel.

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  1. Andre Gehrz: This work is part of a MD thesis

Authors and Affiliations

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

    Alexander Arlt, Andre Gehrz, Susanne Müerköster, Marie-Luise Kruse, Ulrich R Fölsch & Heiner Schäfer

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Correspondence to Heiner Schäfer.

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Arlt, A., Gehrz, A., Müerköster, S. et al. Role of NF-κB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene 22, 3243–3251 (2003). https://doi.org/10.1038/sj.onc.1206390

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