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
- C Brockschmidt1,
- H Hirner1,
- N Huber1,
- T Eismann1,
- A Hillenbrand1,
- G Giamas1,
- B Radunsky1,
- O Ammerpohl2,
- B Bohm2,
- D Henne-Bruns1,
- H Kalthoff2,
- F Leithäuser3,
- A Trauzold2,
- U Knippschild1
- 1Clinic of General-, Visceral- and Transplantation Surgery, University of Ulm, Germany
- 2Department of General- and Thoracic Surgery, Section Molecular Oncology, University Clinic Schleswig-Holstein, Campus Kiel, Germany
- 3Department of Pathology, University of Ulm, Germany
- Dr Uwe Knippschild, Clinic of General-, Visceral- and Transplantation Surgery, University of Ulm, Steinhövelstr. 9, 89075 Ulm, Germany; uwe.knippschild{at}uniklinik-ulm.de
- Revised 20 December 2007
- Accepted 29 December 2007
- Published Online First 18 January 2008
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.
Footnotes
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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).
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Competing interests: None.
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Ethics approval: Animal studies were performed in accordance with the guidelines of the authority of Animal Use and Care Committee.
