title: Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells.
abstract: A major problem in the treatment of cancer arises from quiescent cancer cells that are relatively insensitive to most chemotherapeutic drugs and radiation. Such residual cancer cells can cause tumor regrowth or recurrence when they reenter the cell cycle. Earlier studies showed that levels of the serine/theronine kinase Mirk/dyrk1B are elevated up to 10-fold in quiescent G(0) tumor cells. Mirk uses several mechanisms to block cell cycling, and Mirk increases expression of antioxidant genes that decrease reactive oxygen species (ROS) levels and increase quiescent cell viability. We now show that a novel small molecule Mirk kinase inhibitor blocked tumor cells from undergoing reversible arrest in a quiescent G(0) state and enabled some cells to exit quiescence. The inhibitor increased cycling in Panc1, AsPc1, and SW620 cells that expressed Mirk, but not in HCT116 cells that did not. Mirk kinase inhibition elevated ROS levels and DNA damage detected by increased phosphorylation of the histone protein H2AX and by S-phase checkpoints. The Mirk kinase inhibitor increased cleavage of the apoptotic proteins PARP and caspase 3, and increased tumor cell kill several-fold by gemcitabine and cisplatin. A phenocopy of these effects occurred following Mirk depletion, showing drug specificity. In previous studies Mirk knockout or depletion had no detectable effect on normal tissue, suggesting that the Mirk kinase inhibitor could have a selective effect on cancer cells expressing elevated levels of Mirk kinase.
authors: SUNY Upstate Medical University, Department of Pathology, Syracuse, New York 13210, USA.
authors: Daina Z
authors: DZ
authors: Ewton
authors: Jing
authors: J
authors: Hu
authors: Maria
authors: M
authors: Vilenchik
authors: Xiaobing
authors: X
authors: Deng
authors: Kin-Chun
authors: KC
authors: Luk
authors: Ann
authors: A
authors: Polonskaia
authors: Ann F
authors: AF
authors: Hoffman
authors: Karen
authors: K
authors: Zipf
authors: John F
authors: JF
authors: Boylan
authors: Eileen A
authors: EA
authors: Friedman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005091:Exons; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D000093542:Gemcitabine; D000097603:Dyrk Kinases
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D003841:Deoxycytidine; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000093542:Gemcitabine; D000097603:Dyrk Kinases