The kinase Mirk/Dyrk1B mediates cell survival in pancreatic ductal adenocarcinoma.
Ductal adenocarcinoma of the pancreas is almost uniformly lethal as this cancer is invariably detected at an advanced stage and is resistant to treatment. The serine/threonine kinase Mirk/Dyrk1B has been shown to be antiapoptotic in rhabdomyosarcomas. We have now investigated whether Mirk might mediate survival in another cancer in which Mirk is widely expressed, pancreatic ductal adenocarcinoma. Mirk was an active kinase in each pancreatic cancer cell line where it was detected. Mirk knockdown by RNA interference (RNAi) reduced the clonogenicity of Panc1 pancreatic cancer cells 4-fold and decreased tumor cell number, showing that Mirk mediates survival in these cells. Mirk knockdown by synthetic duplex RNAis in Panc1, AsPc1, and SU86.86 pancreatic cancer cells induced apoptosis and enhanced the apoptosis induced by gemcitibine. Mirk knockdown did not increase the abundance or activation of Akt. However, four of five pancreatic carcinoma cell lines exhibited either elevated Mirk activity or elevated Akt activity, suggesting that pancreatic cancer cells primarily rely on Mirk or Akt for survival signaling. Mirk protein was detected by immunohistochemistry in 25 of 28 cases (89%) of pancreatic ductal adenocarcinoma, with elevated expression in 11 cases (39%). Increased expression of Mirk was seen in pancreatic carcinomas compared with primary cultures of normal ductal epithelium by serial analysis of gene expression and by immunohistochemistry. Thus, Mirk is a survival factor for pancreatic ductal adenocarcinoma. Because knockout of Mirk does not cause embryonic lethality, Mirk is not essential for normal cell growth and may represent a novel therapeutic target.
Deng
Xiaobing
X
Department of Pathology, Upstate Medical University, State University of New York, Syracuse, New York 13210, USA.
Ewton
Daina Z
DZ
Li
Sheena
S
Naqvi
Asghar
A
Mercer
Stephen E
SE
Landas
Steve
S
Friedman
Eileen
E
D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D003593:Cytoplasm / Q000201:enzymology; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors; D000097603:Dyrk Kinases
D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000097603:Dyrk Kinases