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SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer

2010; Cell Press; Volume: 18; Issue: 2 Linguagem: Inglês

10.1016/j.ccr.2010.06.018

1878-3686

Ahmed A. Ahmed, Zhen Lü, Nicholas B. Jennings, Dariush Etemadmoghadam, Luisa Capalbo, Rodrigo Jácamo, Nuno L. Barbosa‐Morais, Xiao-Feng Le, Pablo E. Vivas‐Mejía, Gabriel López-Berestein, Geoffrey Grandjean, Geoffrey Bartholomeusz, Warren S.‐L. Liao, Michael Andreeff, David D.L. Bowtell, David M. Glover, Anil K. Sood, Robert C. Bast,

DNA Repair Mechanisms

Regulators of mitosis have been successfully targeted to enhance response to taxane chemotherapy. Here, we show that the salt inducible kinase 2 (SIK2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, C-Nap1, through S2392 phosphorylation. Interference with the known SIK2 inhibitor PKA induced SIK2-dependent centrosome splitting in interphase while SIK2 depletion blocked centrosome separation in mitosis, sensitizing ovarian cancers to paclitaxel in culture and in xenografts. Depletion of SIK2 also delayed G1/S transition and reduced AKT phosphorylation. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers. We believe these data identify SIK2 as a plausible target for therapy in ovarian cancers.