Ovarian cancer cells, not normal cells, are damaged by Mirk/Dyrk1B kinase inhibition

Abstract

Prior studies had shown that the Mirk/dyrk1B gene is amplified/upregulated in about 75% of ovarian cancers, that protein levels of this kinase are elevated in quiescent G0 cells, and that Mirk maintains tumor cells in quiescence by initiating rapid degradation of cyclin D isoforms and by phosphorylation of a member of the DREAM complex. Depletion of Mirk/dyrk1B led to increased cyclin D levels, an elevated ROS content, and loss of viability. However, many normal cells in vivo are quiescent, so targeting a kinase found in quiescent cells might be problematic. In the current study, Mirk kinase activity was found to be higher in ovarian cancer cells than normal cells. Pharmacological inhibition of Mirk/dyrk1B kinase increased cyclin D levels both in quiescent normal diploid cells and in quiescent CDKN2A-negative ovarian cancer cells, but led to more active CDK4/cyclin D complexes in quiescent ovarian cancer cells, allowing them to escape G0/G1 quiescence, enter cycle with high ROS levels and undergo apoptosis. The ROS scavenger N-acetyl cysteine reduced both the amount of cleaved PARP and the extent of cancer cell loss. In contrast, normal cells were spared because of their expression of CDK inhibitors that blocked unregulated cycling. Quiescent early passage normal ovarian epithelial cells and two strains of quiescent normal diploid fibroblasts remained viable after inhibition of Mirk/dyrk1B kinase, and the few cells that left G0/G1 quiescence accumulated in G2+M. Thus inhibition of Mirk kinase targeted quiescent ovarian cancer cells.

Mirk/dyrk1B Kinase in Ovarian Cancer

“…Depletion of Mirk/dyrk1B led to increased cyclin D levels, an elevated reactive oxygen species content and loss of viability in cancer cells [2,8,19,28]. However, many normal cells in vivo are quiescent, and therefore, targeting a kinase found in quiescent cells might be problematic.…”

The DREAM Complex Mediates GIST Cell Quiescence and Is a Novel Therapeutic Target to Enhance Imatinib-Induced Apoptosis

“…A recently described synthetic inhibitor of DYRK1A, INDY, was found to be active in several in vitro and in vivo models and may show an improved toxicity profile (41). Further support for the concept of quiescence inhibition as a strategy for cancer therapy stems from a previous study in ovarian cancer (42). This report focused on DYRK1A family member DYRK1B, which is overexpressed in ovarian carcinoma cells and has also been shown to be capable of phosphorylating LIN52 (24).…”

“…This report focused on DYRK1A family member DYRK1B, which is overexpressed in ovarian carcinoma cells and has also been shown to be capable of phosphorylating LIN52 (24). Inhibition of DYRK1B by RO5454948, a compound that also inhibits DYRK1A, led to escape from quiescence and an increased apoptotic response (42). Importantly, treatment with RO5454948 did not affect the viability of normal ovarian epithelial cells.…”

Mirk/dyrk1B kinase is upregulated following inhibition of mTOR

“…Mirk levels increase severalfold because of poor growth conditions (13), and Mirk is activated through stress signaling to the Mirk kinase activator MKK3 (20). The mTOR inhibitor RAD001 was the most active through a wide range of concentrations.…”