The kinase Mirk/Dyrk1B mediates cell survival in pancreatic ductal adenocarcinoma Free

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Ductal adenocarcinoma of the pancreas is highly resistant to apoptosis induced by chemotherapeutic drugs or by radiation. Mirk/dyrk1B is a stress-activated kinase which facilitates the survival of regenerating skeletal muscle cells after injury, and mediates survival in pancreatic ductal adenocarcinoma where it is upregulated. Mirk was detected in the majority of cases of pancreatic ductal adenocarcinoma by immunohistochemistry with elevated expression in 39%, and in 7 of 8 pancreatic cancer cell lines, and was seen in fetal pancreatic ductal epithelium. Increased expression of Mirk was also seen in pancreatic carcinomas compared with primary cultures of normal ductal epithelium by serial analysis of gene expression. Mirk knockdown by RNA interference reduced the viability of Panc1 cells several-fold and in a dose-dependent manner, demonstrating that Mirk is a major survival-mediating kinase in these cancer cells. Mirk was an active kinase in each pancreatic cancer cell line where it was detected. Mirk initiated survival signals which inhibited apoptosis in Panc1 cells, while Mirk knockdown increased the apoptosis induced by gemcitibine and nocodazole in these cells. Mirk kinase activity in pancreatic cancer cell lines was inversely related to the activity of the survival kinase Akt, which suggested that pancreatic cancer cells relied primarily on either Mirk or Akt for anti-apoptotic signaling. Mirk does not appear to have wide-spread effects on cell viability as others have found that knock-out of Mirk/dyrk1B was not lethal to the embryo. It is believed by many investigators that carcinoma cells depend on a few dominant survival signals, while normal cells rely on many survival signals, so there might be a therapeutic window which would allow the targeting of survival kinases such as Mirk in cancers. Kinases are readily “druggable”. Because of its properties and expression pattern, Mirk may represent a novel therapeutic target for pancreatic ductal adenocarcinoma.