title: Mirk kinase inhibition targets ovarian cancer ascites.
abstract: The Mirk/dyrk1B gene is commonly amplified or upregulated in ovarian cancers, and Mirk is an active kinase in these cancers. Mirk mediates cancer cell survival by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes, possibly through its transcriptional activator functions. Mirk has the unusual property of being most active in quiescent cancer cells because of marked transcriptional downregulation by Akt/mTOR signaling and by MEK/erk signaling in cycling cells. Metastatic ovarian cancer cells form ascites, non-adherent multicellular aggregates floating within the peritoneal fluid. Most ascites cancer cells are in a reversible quiescent, dormant state, suggesting that Mirk might be expressed in these quiescent cells and thus a therapeutic target. The current studies show that ovarian cancer cell line spheroids that mimic ascites cancer spheroids were largely quiescent in G0/G1, and enriched in Mirk and the quiescence proteins, p130/Rb2 and the CDKI p27. Mirk kinase inhibition in spheroids made from established cell lines and in patient-derived ascites cancer cell spheroids reduced spheroid volume, disrupted spheroid structure to single cells, increased apoptosis, and decreased cell numbers. Earlier studies had shown that the mTOR inhibitor RAD001 increased transcription of the Mirk/dyrk1B gene, so treatments combined RAD001 with the most active Mirk kinase inhibitor. The number of ascites cells from 9 patients was reduced a similar amount by cisplatin, Mirk kinase inhibition or RAD001, but reduced substantially more, about 90%, by concurrent treatment with both the Mirk kinase inhibitor EHT5372 and RAD001. Addition of RAD001 increased the amount of toxic ROS induced by Mirk kinase inhibition. Two ascites samples taken one month apart gave similar drug responses, showing reproducibility of the techniques. Thus Mirk/dyrk1B kinase may be a therapeutic target in ovarian cancer ascites.
authors: Department of Pathology, Upstate Medical University, Syracuse, N.Y., USA.
authors: Xiaobing
authors: X
authors: Deng
authors: Department of Pathology, Upstate Medical University, Syracuse, N.Y., USA.
authors: Jing
authors: J
authors: Hu
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology Upstate Medical University, Syracuse, N.Y., USA.
authors: Mary J
authors: MJ
authors: Cunningham
authors: Department of Pathology, Upstate Medical University, Syracuse, N.Y., USA.
authors: Eileen
authors: E
authors: Friedman
keywords: Mirk/dyrk1B; ascites; kinase; ovarian cancer