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

作者：Brockschmidt C; Hirner H; Huber N; Eismann T; Hillenbrand A; Giamas G; Radunsky B; Ammerpohl O; Bohm B; Henne Bruns D; Kalthoff H; Leithaeuser F; Trauzold A; Knippschild U^*

来源：Gut, 2008, 57(6): 799-806.

DOI：10.1136/gut.2007.123695

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 (CK1 delta/epsilon) 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: CK1 delta/epsilon 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 CK1 delta/epsilon are highly expressed in pancreatic tumour cell lines and in higher graded PDACs. Inhibition of CK1 delta/epsilon 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.

• 出版日期2008-6