SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer

被引：122

作者：

Ahmed, Ahmed Ashour ^{[1
,4
,5
]}

Lu, Zhen ^{[1
]}

Jennings, Nicholas B. ^{[2
]}

Etemadmoghadam, Dariush ^{[7
]}

Capalbo, Luisa ^{[6
]}

Jacamo, Rodrigo O. ^{[3
]}

Barbosa-Morais, Nuno ^{[8
]}

Le, Xiao-Feng ^{[1
]}

Vivas-Mejia, Pablo ^{[1
]}

Lopez-Berestein, Gabriel ^{[1
]}

Grandjean, Geoffrey ^{[1
]}

Bartholomeusz, Geoffrey ^{[1
]}

Liao, Warren ^{[1
]}

Andreeff, Michael ^{[3
]}

Bowtell, David ^{[7
]}

Glover, David M. ^{[6
]}

Sood, Anil K. ^{[2
]}

Bast, Robert C., Jr. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA

[4] Univ Cambridge, Hutchison MRC Res Ctr, Dept Oncol, Cambridge CB2 0XZ, England

[5] Univ Cambridge, Rosie Hosp, Dept Obstet & Gynaecol, Cambridge CB2 0SW, England

[6] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England

[7] Peter MacCallum Canc Ctr, Canc Genom & Genet Lab, Melbourne, Vic 8006, Australia

[8] Univ Cambridge, Canc Res UK Cambridge Res Inst, Dept Oncol, Computat Biol Grp,Li Ka Shing Ctr, Cambridge CB2 0RE, England

来源：

CANCER CELL | 2010年 / 18卷 / 02期

基金：

英国医学研究理事会;

关键词：

CELL-CYCLE PROGRESSION; ALPHA REGULATORY SUBUNIT; COACTIVATOR TORC2; PROTEIN-KINASE; RII-ALPHA; S-PHASE; PACLITAXEL; CREB; CYCLOPHOSPHAMIDE; PHOSPHORYLATION;

D O I：

10.1016/j.ccr.2010.06.018

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：109 / 121

页数：13

共 32 条

[1] The extracellular matrix protein TGFBI induces microtubule stabilization and sensitizes ovarian cancers to paclitaxel [J].

Ahmed, Ahmed Ashour ;

Mills, Anthony D. ;

Ibrahim, Ashraf E. K. ;

Temple, Jillian ;

Blenkiron, Cherie ;

Vias, Maria ;

Massie, Charlie E. ;

Iyer, N. Gopalakrishna ;

McGeoch, Adam ;

Crawford, Robin ;

Nicke, Barbara ;

Downward, Julian ;

Swanton, Charles ;

Bell, Stephen D. ;

Earl, Helena M. ;

Laskey, Ronald A. ;

Caldas, Carlos ;

Brenton, James D. .

CANCER CELL, 2007, 12 (06) :514-527

[2] Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit [J].

Bekier, Michael E. ;

Fischbach, Robert ;

Lee, Jennifer ;

Taylor, William R. .

MOLECULAR CANCER THERAPEUTICS, 2009, 8 (06) :1646-1654

[3] Genome-wide survey of protein kinases required for cell cycle progression [J].

Bettencourt-Dias, M ;

Giet, R ;

Sinka, R ;

Mazumdar, A ;

Lock, WG ;

Balloux, F ;

Zafiropoulos, PJ ;

Yamaguchi, S ;

Winter, S ;

Carthew, RW ;

Cooper, M ;

Jones, D ;

Frenz, L ;

Glover, DM .

NATURE, 2004, 432 (7020) :980-987

[4] A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours [J].

Blagden, S. P. ;

Molife, L. R. ;

Seebaran, A. ;

Payne, M. ;

Reid, A. H. M. ;

Protheroe, A. S. ;

Vasist, L. S. ;

Williams, D. D. ;

Bowen, C. ;

Kathman, S. J. ;

Hodge, J. P. ;

Dar, M. M. ;

de Bono, J. S. ;

Middleton, M. R. .

BRITISH JOURNAL OF CANCER, 2008, 98 (05) :894-899

[5]

Carlson CR, 2001, J CELL SCI, V114, P3243

[6]

de Castro I.Perez., 2008, CURR OPIN PHARMACOL, V8, P375, DOI DOI 10.1016/j.coph.2008.06.013

[7] Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2 [J].

Dentin, Renaud ;

Liu, Yi ;

Koo, Seung-Hoi ;

Hedrick, Susan ;

Vargas, Thomas ;

Heredia, Jose ;

Yates, John, III ;

Montminy, Marc .

NATURE, 2007, 449 (7160) :366-+

[8] C-Nap1, a novel centrosomal coiled-coil protein and candidate substrate of the cell cycle-regulated protein kinase Nek2 [J].

Fry, AM ;

Mayor, T ;

Meraldi, P ;

Stierhof, YD ;

Tanaka, K ;

Nigg, EA .

JOURNAL OF CELL BIOLOGY, 1998, 141 (07) :1563-1574

[9] A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators [J].

Fry, AM ;

Meraldi, P ;

Nigg, EA .

EMBO JOURNAL, 1998, 17 (02) :470-481

[10] Aurora kinases as anticancer drug targets [J].

Gautschi, Oliver ;

Heighway, Jim ;

Mack, Philip C. ;

Purnell, Phillip R. ;

Lara, Primo N., Jr. ;

Gandara, David R. .

CLINICAL CANCER RESEARCH, 2008, 14 (06) :1639-1648

← 1 2 3 4 →