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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.

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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.

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