Depleting Mirk Kinase Increases Cisplatin Toxicity in Ovarian Cancer Cells.

Cisplatin-based regimens are the standard of care for epithelial carcinoma of the ovary. Since cisplatin is known to increase intracellular levels of toxic reactive oxygen species (ROS), an increase in cisplatin toxicity selectively in cancer cells could result from further increasing the cisplatin-elevated ROS levels by targeting antioxidant genes upregulated in ovarian cancers. The serine/threonine kinase Mirk/dyrk1B is a transcriptional co-activator which increased the expression of the antioxidant genes superoxide dismutase 2 and ferroxidase in ovarian cancer cells. As a result, depletion of Mirk increased cellular ROS levels in each of 4 ovarian cancer cell lines. Mirk depletion averaged only about 4 fold, yet combined with cisplatin treatment enabled low levels of drug to increase ROS to toxic levels in both SKOV3 and TOV21G ovarian cancer cells. Lowering ROS levels by treatment with N-acetyl cysteine limited cisplatin toxicity, resulting in higher cell numbers and decreased cleavage of the apoptotic proteins PARP and caspase 3. Mirk has also been shown to block cells in G1 by inducing proteolysis of cyclin D1. Mirk depletion increased cyclin D1 levels in 3 of 4 ovarian cancer cell lines, implying that some Mirk depleted cells could more readily enter cycle, potentially increasing their sensitivity to cisplatin. Since Mirk is upregulated in a large subset of human ovarian cancers, but is expressed at low levels in most normal tissues, and embryonic knockout of Mirk results in viable and fertile mice, targeting Mirk may sensitize ovarian cancers to lower levels of cisplatin, while sparing normal tissues.