title: SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer.
abstract: 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.
authors: Department of Experimental Therapeutics, M.D. Anderson Cancer Center, University of Texas, Houston, 77030, USA. ahmed.ahmed@obs-gyn.ox.ac.uk
authors: Ahmed Ashour
authors: AA
authors: Ahmed
authors: Zhen
authors: Z
authors: Lu
authors: Nicholas B
authors: NB
authors: Jennings
authors: Dariush
authors: D
authors: Etemadmoghadam
authors: Luisa
authors: L
authors: Capalbo
authors: Rodrigo O
authors: RO
authors: Jacamo
authors: Nuno
authors: N
authors: Barbosa-Morais
authors: Xiao-Feng
authors: XF
authors: Le
authors: Pablo
authors: P
authors: Vivas-Mejia
authors: Gabriel
authors: G
authors: Lopez-Berestein
authors: Geoffrey
authors: G
authors: Grandjean
authors: Geoffrey
authors: G
authors: Bartholomeusz
authors: Warren
authors: W
authors: Liao
authors: Michael
authors: M
authors: Andreeff
authors: David
authors: D
authors: Bowtell
authors: David M
authors: DM
authors: Glover
authors: Anil K
authors: AK
authors: Sood
authors: Robert C
authors: RC
authors: Bast
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018385:Centrosome / Q000201:enzymology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D008941:Spindle Apparatus; D014183:Transplantation, Heterologous
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D034741:RNA, Small Interfering; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel