TY - JOUR
T1 - SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer
AU - Ahmed, Ahmed Ashour
AU - Lu, Zhen
AU - Jennings, Nicholas B.
AU - Etemadmoghadam, Dariush
AU - Capalbo, Luisa
AU - Jacamo, Rodrigo O.
AU - Barbosa-Morais, Nuno
AU - Le, Xiao Feng
AU - Vivas-Mejia, Pablo
AU - Lopez-Berestein, Gabriel
AU - Grandjean, Geoffrey
AU - Bartholomeusz, Geoffrey
AU - Liao, Warren
AU - Andreeff, Michael
AU - Bowtell, David
AU - Glover, David M.
AU - Sood, Anil K.
AU - Bast, Robert C.
N1 - Funding Information:
We would like to thank Dr. E. Nigg and Dr. M. Bornens for giving valuable reagents. We also thank Dr. R. Laskey, Dr. B. Hassan, and Dr. G. Smith for helpful comments on the manuscript. We thank Dr. G. Tzolovsky for technical help. This work was funded by Cancer Research UK, the University of Cambridge, the Zarrow Foundation, the Ovarian Cancer Research Fund Program Project Development Grant, and the University of Texas M.D. Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence (P50 CA083639) and the Addenbrooke's Charitable Trust. A.A.A. is a Cancer Research UK Clinician Scientist. The AOCS was supported by The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, the Cancer Council Tasmania, and the National Health and Medical Research Council of Australia (NHMRC). The authors would like to thank Dr. M. Deery and members of the Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, members of the time-lapse microscopy facility (supported by NCI core grant 5P30CA016672-29), and members of the siRNA screening facility at the University of Texas M.D. Anderson Cancer Center for technical assistance.
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
KW - Cellbio
KW - Cellcycle
KW - Humdisease
UR - http://www.scopus.com/inward/record.url?scp=77955530763&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955530763&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2010.06.018
DO - 10.1016/j.ccr.2010.06.018
M3 - Article
C2 - 20708153
AN - SCOPUS:77955530763
SN - 1535-6108
VL - 18
SP - 109
EP - 121
JO - Cancer cell
JF - Cancer cell
IS - 2
ER -