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Mirk/Dyrk1B Maintains the Viability of Quiescent Pancreatic Cancer Cells by Reducing Levels of Reactive Oxygen Species

Pathology Department, Upstate Medical University, State University of New York, Syracuse, New York

Request for reprints: Eileen Friedman, Upstate Medical University, Pathology Department, 2305 Weiskotten Hall, 750 East Adams Street, Syracuse, NY 13210. Phone: 315-464-7148; Fax: 315-464-8419; E-mail: friedmae{at}upstate.edu.

Key Words: Mirk • dyrk1B • G₀ • quiescence • ROS.

The kinase Mirk/dyrk1B mediated the clonogenic growth of pancreatic cancer cells in earlier studies. It is now shown that Mirk levels increased 7-fold in SU86.86 pancreatic cancer cells when over a third of the cells were accumulated in a quiescent G₀ state, defined by Hoechst/Pyronin Y staining. Depletion of Mirk by a doxycycline-inducible short hairpin RNA increased the G₀ fraction to 50%, suggesting that Mirk provided some function in G₀. Mirk reduced the levels of reactive oxygen species (ROS) in quiescent cultures of SU86.86 cells and of Panc1 cells by increasing transcription of the antioxidant genes ferroxidase, superoxide dismutase (SOD)2, and SOD3. These genes were functional antioxidant genes in pancreatic cancer cells because ectopic expression of SOD2 and ferroxidase in Mirk-depleted cells lowered ROS levels. Quiescent pancreatic cancer cells quickly lost viability when depleted of Mirk because of elevated ROS levels, exhibiting up to 4-fold less colony-forming activity and 4-fold less capability for dye exclusion. As a result, reduction of ROS by N-acetyl cysteine led to more viable cells. Mirk also destabilizated cyclin D1 and D3 in quiescent cells. Thus, quiescent pancreatic cancer cells depleted of Mirk became less viable because they were damaged by ROS, and had increased levels of G₁ cyclins to prime cells to escape quiescence. [Cancer Res 2009;69(8):3317–24]

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