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.
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.


OBJECTIVE
We analysed the expression levels of CK1 delta and epsilon (CK1delta/in) 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
CK1delta/in 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 CK1delta/in are highly expressed in pancreatic tumour cell lines and in higher graded PDACs. Inhibition of CK1delta/in 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.
Brockschmidt
C
C
Clinic of General-, Visceral- and Transplantation Surgery, University of Ulm, Steinhövelstr. 9, 89075 Ulm, Germany.
Hirner
H
H
Huber
N
N
Eismann
T
T
Hillenbrand
A
A
Giamas
G
G
Radunsky
B
B
Ammerpohl
O
O
Bohm
B
B
Henne-Bruns
D
D
Kalthoff
H
H
Leithäuser
F
F
Trauzold
A
A
Knippschild
U
U
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000556:secondary; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008207:Lymphatic Metastasis; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; C411652:IC 261; D007211:Indoles; D019014:fas Receptor; D003841:Deoxycytidine; D010696:Phloroglucinol; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta; D000093542:Gemcitabine