Authors:
Ahmed AA, Lu Z, Jennings NB, Etemadmoghadam D, Capalbo L, Jacamo RO, Barbosa-Morais N, Le XF; Australian Ovarian Cancer Study Group, Vivas-Mejia P, Lopez-Berestein G, Grandjean G, Bartholomeusz G, Liao W, Andreeff M, Bowtell D, Glover DM, Sood AK, & Bast RC Jr
Summary:
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.
Source:
Cancer Cell; 18(2), 109-121 (08/09/10))