Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Oncogene Submit manuscript

A Corrigendum to this article was published on 18 April 2002

This article has been updated

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Change history

Abbreviations

FITC:

fluorescein isothiocyanate

IKK:

IκB kinase

NF-κB:

nuclear factor κB

PVDF:

polyvinylidene difluoride

References

  • Barkett M and Gilmore TD. . 1999 Oncogene 18: 6910–6925.

  • Das KC, Guo XL and White CW. . 1998 J. Biol. Chem. 273: 34639–34645.

  • Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, Scheidereit C and Leutz A. . 1999 Oncogene 18: 3316–3323.

  • Dingemans AM, Witlox MA, Stallaert RA, van der Valk P, Postmus PE and Giaccone G. . 1999 Clin. Cancer Res. 5: 2048–2058.

  • Egawa N, Maillet B, VanDamme B, De Greve J and Klöppel G. . 1996 Virchows Arch. 429: 59–68.

  • Estival A, Clerc P, Vaysse N, Tam JP and Clemente F. . 1992 Gastroenterology 103: 1851–1859.

  • Fry AM, Chresta CM, Davies SM, Walker MC, Harris AL, Hartley JA, Masters JR and Hickson ID. . 1991 Cancer Res. 51: 6592–6595.

  • Hellerbrand C, Jobin C, Iimuro Y, Licato L, Sartor RB and Brenner DA. . 1998 Hepatology 27: 1285–1295.

  • Jeremias I, Kupatt C, Baumann B, Herr I, Wirth T and Debatin KM. . 1998 Blood 91: 4624–4631.

  • Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G, Thiele HG, Honold G, Pantel K, Riethmüller G, Scherer E, Maurer J, Maacke H and Deppert W. . 1993 Oncogene 8: 289–298.

  • Kingma PS and Osheroff N. . 1998 Biochim. Biophys. Acta 1400: 223–232.

  • Kothny-Wilkes G, Kulms D, Poppelmann B, Luger TA, Kubin M and Schwarz T. . 1998 J. Biol. Chem. 273: 29247–29253.

  • Krappmann D, Emmerich F, Kordes U, Scharschmidt E, Dörken B and Scheidereit C. . 1999 Oncogene 18: 943–953.

  • Lam V, McPherson JP, Salmena L, Lees J, Chu W, Sexsmith E, Hedley DW, Freedman MH, Reed JC, Malkin D and Goldenberg GJ. . 1999 Leuk. Res. 23: 871–880.

  • Liu ZG, Hsu H, Goeddel DV and Karin M. . 1996 Cell 87: 565–576.

  • Long BH, Wang L, Lorico A, Wang RC, Brattain MG and Casazza AM. . 1991 Cancer Res. 51: 5275–5283.

  • Mao Y, Yu C, Hsieh TS, Nitiss JL, Liu AA, Wang H and Liu LF. . 1999 Biochemistry 38: 10793–10800.

  • Mazo A, Fujii Y, Shimotake J and Escribano MJ. . 1991 Pancreas 6: 37–45.

  • McDade TP, Perugini RA, Vittimberga Jr FJ, Carrigan RC and Callery MP. . 1999 J. Surg. Res. 83: 56–61.

  • Murphy M, Ahn J, Walker KK, Hoffman WH, Evans RM, Levine AJ and George DL. . 1999 Genes Dev. 13: 2490–2501.

  • Pahl HL, Krauss B, Schulze-Osthoff K, Decker T, Traenckner EB, Vogt M, Myers C, Parks T, Warring P, Muhlbacher A, Czernilofsky AP and Baeuerle PA. . 1996 J. Exp. Med. 183: 1829–1840.

  • Salminen A, Tapiola T, Korhonen P and Suuronen T. . 1998 Brain Res. Mol. Brain Res. 30: 203–206.

  • Schäfer H, Diebel J, Arlt A, Trauzold A and Schmidt WE. . 1998 FEBS Lett. 436: 139–143.

  • Sheppard KA, Rose DW, Haque ZK, Kurokawa R, McInerney E, Westin S, Thanos D, Rosenfeld MG, Glass CK and Collins T. . 1999 Mol. Cell. Biol. 19: 6367–6378.

  • Ungefroren H, Voss M, Jansen M, Roeder C, Henne-Bruns D, Kremer B and Kalthoff H. . 1998 Cancer Res. 58: 1741–1749.

  • Wahl C, Liptay S, Adler G and Schmid RM. . 1998 J. Clin. Invest. 101: 1163–1174.

  • Wang CY, Mayo MW and Baldwin Jr AS. . 1996 Science 274: 784–787.

  • Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR and Chiao PJ. . 1999a Clin. Cancer Res. 5: 119–127.

  • Wang CY, Guttridge DC, Mayo MW and Baldwin Jr AS. . 1999b Mol. Cell. Biol. 19: 5923–5929.

  • Widlak P, Gaynor RB and Garrard WT. . 1997 J. Biol. Chem. 272: 17654–17661.

  • Zong WX, Bash J and Gelinas C. . 1998 Cell Death Differ. 5: 963–972.

Download references

Acknowledgements

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

Author information

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

Authors
  1. Alexander Arlt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jens Vorndamm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maike Breitenbroich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulrich R Fölsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Holger Kalthoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wolfgang E Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heiner Schäfer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204168

  • Springer Nature Limited

Keywords

This article is cited by

Search

Navigation