SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer.
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.
Ahmed
Ahmed Ashour
AA
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, University of Texas, Houston, 77030, USA. ahmed.ahmed@obs-gyn.ox.ac.uk
Lu
Zhen
Z
Jennings
Nicholas B
NB
Etemadmoghadam
Dariush
D
Capalbo
Luisa
L
Jacamo
Rodrigo O
RO
Barbosa-Morais
Nuno
N
Le
Xiao-Feng
XF
Vivas-Mejia
Pablo
P
Lopez-Berestein
Gabriel
G
Grandjean
Geoffrey
G
Bartholomeusz
Geoffrey
G
Liao
Warren
W
Andreeff
Michael
M
Bowtell
David
D
Glover
David M
DM
Sood
Anil K
AK
Bast
Robert C
RC
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
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