You are here

  • Home
  • Archive
  • Volume 57, Issue 6
  • Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo

Article Text

Article menu
Download PDFPDF
Pancreas
Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo
  1. C Brockschmidt1,
  2. H Hirner1,
  3. N Huber1,
  4. T Eismann1,
  5. A Hillenbrand1,
  6. G Giamas1,
  7. B Radunsky1,
  8. O Ammerpohl2,
  9. B Bohm2,
  10. D Henne-Bruns1,
  11. H Kalthoff2,
  12. F Leithäuser3,
  13. A Trauzold2,
  14. U Knippschild1
  1. 1
    Clinic of General-, Visceral- and Transplantation Surgery, University of Ulm, Germany
  2. 2
    Department of General- and Thoracic Surgery, Section Molecular Oncology, University Clinic Schleswig-Holstein, Campus Kiel, Germany
  3. 3
    Department of Pathology, University of Ulm, Germany
  1. Dr Uwe Knippschild, Clinic of General-, Visceral- and Transplantation Surgery, University of Ulm, Steinhövelstr. 9, 89075 Ulm, Germany; uwe.knippschild{at}uniklinik-ulm.de

Abstract

Background: Pancreatic ductal adenocarcinomas (PDACs) are highly resistant to treatment due to changes in various signalling pathways. CK1 isoforms play important regulatory roles in these pathways.

Aims: We analysed the expression levels of CK1 delta and epsilon (CK1δ/∊) in pancreatic tumour cells in order to validate the effects of CK1 inhibition by 3-[2,4,6-(trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261) on their proliferation and sensitivity to anti-CD95 and gemcitabine.

Methods: CK1δ/∊ expression levels were investigated by using western blotting and immunohistochemistry. Cell death was analysed by FACS analysis. Gene expression was assessed by real-time PCR and western blotting. The putative anti-tumoral effects of IC261 were tested in vivo in a subcutaneous mouse xenotransplantation model for pancreatic cancer.

Results: We found that CK1δ/∊ are highly expressed in pancreatic tumour cell lines and in higher graded PDACs. Inhibition of CK1δ/∊ by IC261 reduced pancreatic tumour cell growth in vitro and in vivo. Moreover, IC261 decreased the expression levels of several anti-apoptotic proteins and sensitised cells to CD95-mediated apoptosis. However, IC261 did not enhance gemcitabine-mediated cell death either in vitro or in vivo.

Conclusions: Targeting CK1 isoforms by IC261 influences both pancreatic tumour cell growth and apoptosis sensitivity in vitro and the growth of induced tumours in vivo, thus providing a promising new strategy for the treatment of pancreatic tumours.

https://doi.org/10.1136/gut.2007.123695

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Footnotes

    • Funding: This work was supported by grants from the Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe to Uwe Knippschild (SFB 518/B15, 10-2237 Kn), and to Holger Kalthoff (SFB 415/A3).

    • Competing interests: None.

    • Ethics approval: Animal studies were performed in accordance with the guidelines of the authority of Animal Use and Care Committee.

    Linked Articles