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

被引：137

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 [肿瘤学];

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

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