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Mirk kinase inhibition blocks the in vivo growth of pancreatic cancer cells.


ABSTRACT: The Mirk/dyrk1B gene is upregulated and sometimes amplified in pancreatic ductal carcinomas. In poor microenvironmental conditions Mirk mediates cell survival by maintaining cancer cells in a largely quiescent, noncycling state and by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes. Premature entry into cycle, increased ROS levels, DNA damage, and apoptosis follow Mirk kinase depletion or inhibition. Mirk kinase inhibitor EHT5372 treated Panc1 spheroids lost quiescence markers coincident with an increase in cyclin A showing entry into cycle, and exhibited DNA damage, apoptosis and smaller size. EHT5372 treatment in vivo led to an increased fraction of Ki67 positive, cycling cells in Panc1 xenografts whose size was reduced. Pdx-1-cre LSL/KrasG12D/Ink4a/Arf null B6 mice always develop pancreatic cancer, allowing only 30% survival by 8 weeks, while each of the Mirk kinase inhibitor treated mice survived 8 weeks. Mirk inhibition led to a roughly four-fold increase in tumor ?SMA-positive fibroblasts and large stromal collagen-rich infiltrates in the pancreas that can restrain tumor growth. The mTOR inhibitor RAD001 alone, or together with EHT5372, reduced pancreatic cancer size 30-fold, while the drug combination reduced the number of microscopic tumor foci 2-fold compared to RAD001 alone.

SUBMITTER: Deng X 

PROVIDER: S-EPMC4209603 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Mirk kinase inhibition blocks the in vivo growth of pancreatic cancer cells.

Deng Xiaobing X   Friedman Eileen E  

Genes & cancer 20140901 9-10


The Mirk/dyrk1B gene is upregulated and sometimes amplified in pancreatic ductal carcinomas. In poor microenvironmental conditions Mirk mediates cell survival by maintaining cancer cells in a largely quiescent, noncycling state and by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes. Premature entry into cycle, increased ROS levels, DNA damage, and apoptosis follow Mirk kinase depletion or inhibition. Mirk kinase inhibitor EHT5372 treated Panc1 spheroid  ...[more]

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