SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer
- Creators
- Ahmed, Ahmed Ashour
- Lu, Zhen
- Jennings, Nicholas B.
- Etemadmoghadam, Dariush
- Capalbo, Luisa
- Jacamo, Rodrigo O.
- Barbosa-Morais, Nuno
- Le, Xiao-Feng
- Vivas-Mejia, Pablo
- Lopez-Berestein, Gabriel
- Grandjean, Geoffrey
- Bartholomeusz, Geoffrey
- Liao, Warren
- Andreeff, Michael
- Bowtell, David
-
Glover, David M.
- Sood, Anil K.
- Bast, Robert C.
- Australian Ovarian Cancer Study Group
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.
Additional Information
© 2010 Elsevier. Under an Elsevier user license. Received 4 January 2010, Revised 2 May 2010, Accepted 2 July 2010, Available online 16 August 2010. 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. Detailed additional methods are available as Supplemental Information.Attached Files
Accepted Version - nihms229878.pdf
Supplemental Material - 1-s2.0-S1535610810002746-mmc1.pdf
Supplemental Material - 1-s2.0-S1535610810002746-mmc2.xls
Supplemental Material - 1-s2.0-S1535610810002746-mmc3.xls
Supplemental Material - 1-s2.0-S1535610810002746-mmc4.xls
Supplemental Material - 1-s2.0-S1535610810002746-mmc5.xls
Supplemental Material - 1-s2.0-S1535610810002746-mmc6.mp4
Supplemental Material - 1-s2.0-S1535610810002746-mmc7.mp4
Supplemental Material - 1-s2.0-S1535610810002746-mmc8.mp4
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Additional details
- PMCID
- PMC3954541
- Eprint ID
- 105607
- DOI
- 10.1016/j.ccr.2010.06.018
- Resolver ID
- CaltechAUTHORS:20200928-150625661
- Cancer Research UK
- University of Cambridge
- Zarrow Foundation
- Ovarian Cancer Research Fund
- NIH
- P50 CA083639
- Addenbrooke's Charitable Trust
- Cancer Council Victoria
- Queensland Cancer Fund
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Foundation of Western Australia
- Cancer Council Tasmania
- National Health and Medical Research Council (NHMRC)
- NIH
- 5P30CA016672-29
- Created
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2020-09-29Created from EPrint's datestamp field
- Updated
-
2021-11-16Created from EPrint's last_modified field