Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1β and NO lead to inactivation of caspases

Oncogene volume 25, pages 3973–3981 (2006)Cite this article

A Corrigendum to this article was published on 03 August 2006

Abstract

Pancreatic cancer exhibits profound chemoresistance resulting either from pre-existing (intrinsic) mechanisms, or from anticancer drug treatment itself (acquired chemoresistance). To identify molecular alterations leading to acquired chemoresistance, the chemosensitive pancreatic carcinoma cell line PT45-P1 was exposed to low-dose treatment with etoposide for 6 weeks. Afterwards, these cells (PT45-P1res) were much more resistant to high-dose treatment with anticancer drugs than parental cells. Among several differentially expressed genes in PT45-P1res cells, IL-1β was most significantly upregulated, a finding in line with our previous observation that IL-1β accounts for intrinsic chemoresistance of pancreatic carcinoma cells. Elevated IL-1β expression in PT45-P1res cells was confirmed by real-time PCR and ELISA, and treatment with the IL-1 receptor antagonist restored drug-induced apoptosis. The increased IL-1β secretion was accompanied by an elevated formation of nitric oxide (NO) and a NO-dependent inhibition of the etoposide-induced caspase-3/-7/-8/-9 activity. Caspase activation was restored either by the iNOS inhibitor 1400W, the reducing agent dithiothreitol or the IL-1 receptor antagonist, resulting in greater sensitivity towards anticancer drug treatment. Conversely, IL-1β or the NO-donor SNAP decreased caspase activation and apoptosis in etoposide-treated PT45-P1 cells. These data confirm IL-1β and NO as determinants of chemoresistance in pancreatic cancer, and indicate that the intrinsic and acquired chemoresistance rely to some extent on common molecular targets beneficial for improved therapeutical strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

Abbreviations

DTT:

Dithiothreitol

IL-1β:

Interleukin 1 beta

IL1-RA:

IL-1 receptor antagonist

NF-κB:

Nuclear factor kappa B

NO:

Nitric oxide

PDAC:

Pancreatic ductal adenocarcinoma

SNAP:

S-Nitroso-N-acetyl-D,L-penicillamine

References

  • Arlt A, Gehrz A, Müerköster S, Vorndamm J, Kruse M-L, Fölsch UR et al. (2003). Oncogene 22: 3243–3251.

  • Arlt A, Vorndamm J, Müerköster S, Yu H, Schmidt WE, Fölsch UR et al. (2002). Cancer Res 62: 910–916.

  • Arlt A, Vorndamm J, Breitenbroich M, Fölsch UR, Kalthoff H, Schmidt WE et al. (2001). Oncogene 20: 859–868.

  • Banerjee D, Mayer-Kuckuk P, Capiaux G, Budak-Alpdogan T, Gorlick R, Bertino JR . (2002). Biochim. Biophys. Acta 1587: 164–173.

  • Blaszkowsky L . (1998). Front. Biosci. 3: 214–225.

  • Bramhal SR, Allum WH, Jones AG, Allwood A, Cummins C, Neoptolemos JP . (1995). Br J Surg 82: 111–115.

  • Brand RE, Tempero MA . (1998). Curr Opin Oncol 10: 362–366.

  • Brown JM, Attardi LD . (2005). Nat Rev Cancer 5: 231–237.

  • Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C et al. (2004). Mol Cell Biol 24: 2875–2889.

  • Friesen C, Fulda S, Debatin KM . (1999). Leukemia 13: 1854–1858.

  • Jaiswal M, LaRusso NF, Gores GJ . (2001). Am J Physiol Gastrointest Liver Physiol 281: G626–634.

  • Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G et al. (1993). Oncogene 8: 289–298.

  • Kang HC, Kim IJ, Park JH, Shin Y, Ku JL, Jung MS et al. (2004). Clin Cancer Res 10: 272–284.

  • Kim K-M, Kim PKM, Kwon YG, Bai S-K, Nam W-D, Kim Y-M . (2002). J Biochem Mol Biol 35: 127–133.

  • Kim R, Emi M, Tanabe K, Toge T . (2004). Cancer 101: 2491–2502. Cancer Res 59: 3505–351.

  • Kolb JP . (2000). Leukemia 14: 1685–1694.

  • Li JL, Billiar TR, Talanian RV, Kim YM . (1997). Biochem Biophys Res Commun 240: 419–424.

  • Lillemore KD . (1998). Surg Oncol Clin North Am 7: 199–216.

  • Maejima Y, Adachi S, Morikawa K, Ito H, Isobe M . (2005). J Mol Cell Cardiol 38: 163–174.

  • Medema JP, de Jong J, van Hall T, Melief CJM, Offringa R . (1999). J Exp Med 7: 1033–1038.

  • Morisaki T, Katano M . (2003). Curr Med Chem 10: 2517–2521.

  • Müerköster S, Arlt A, Sipos B, Witt M, Großmann M, Klöppel G et al. (2005). Cancer Res F 65: 1316–1324.

  • Müerköster S, Arlt A, Witt M, Gehrz A, Haye S, March C et al. (2003). Int J Cancer 104: 469–476, 2003.

  • Müerköster S, Wegehenkel K, Arlt A, Witt M, Sipos B, Kruse ML et al. (2004). Cancer Res 64: 1331–1337.

  • Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H et al. (2001). Lancet 358: 1576–1585.

  • Parker SL, Tong T, Bolden S, Wingo PA . (1997). CA Cancer J Clin 47: 5–27.

  • Poppenborg H, Knupfer MM, Galla HJ, Ernst J, Wolff A . (1999). Cytokine 11: 689–695.

  • Schäfer H, Arlt A, Trauzold A, Hünermann-Jansen A, Schmidt WE . (1999). Biochem Biophys Res Commun 262: 139–145.

  • Schmid RM, Adler G . (2000). Gastroenterology 118: 1208–1228.

  • Soengas MS, Lowe SW . (2003). Oncogene 22: 3138–3151.

  • Sreedhar AS, Csermely P . (2004). Pharmacol Ther 101: 227–257.

  • Stamler JS . (1994). Cell 78: 931–936.

  • Turzanski J, Grundy M, Russell NH, Pallis M . (2004). Leukemia 18: 1662–1670.

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

  • Yan Y, Mahotka C, Heikaus S, Shibita T, Wethkamp N, Liebmann J et al. (2004). Br J Cancer 91: 1349–1357.

Download references

Acknowledgements

This work was supported by the German Research Society DFG Scha 677/7-2 (HS).

Author information

Authors and Affiliations

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

    S Sebens Müerköster, J Lust, A Arlt, M Witt, T Sebens, U R Fölsch & H Schäfer

  2. 1st Department of Medicine, Mucosal Immunology Research Group, UKSH, Campus Kiel, Kiel, Germany

    R Häsler & S Schreiber

Authors
  1. S Sebens Müerköster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Lust
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Arlt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Häsler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Witt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Sebens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Schreiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. U R Fölsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Schäfer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Schäfer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Müerköster, S., Lust, J., Arlt, A. et al. Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1β and NO lead to inactivation of caspases. Oncogene 25, 3973–3981 (2006). https://doi.org/10.1038/sj.onc.1209423

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209423

Keywords

This article is cited by

Search

Advanced search

Quick links