Background: Pancreatic ductal adenocarcinomas (PDACs) are highly resistant to therapy due to changes in various signalling pathways. CK1 isoforms are playing important regulatory roles in these pathways.
Aims: We thought to analyse the expression levels of CK1 delta and epsilon (CK1δ/∊) in pancreatic tumour cells and 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 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 neither in vitro nor 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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