BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin.
BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin.
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DOI：
10.3802/jgo.2012.23.1.35
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发表时间：
2012-01
影响因子：
3.9
通讯作者：
Lancaster JM
中科院分区：
文献类型：
--
作者：
Bansal N;Marchion DC;Bicaku E;Xiong Y;Chen N;Stickles XB;Sawah EA;Wenham RM;Apte SM;Gonzalez-Bosquet J;Judson PL;Hakam A;Lancaster JM
BCL2家族蛋白是细胞凋亡的关键介质，因此被认为是癌细胞化学敏感性的决定因素。最近有研究表明，BCL2细胞死亡拮抗剂（BAD）蛋白的磷酸化状态可能影响卵巢癌（OVCA）细胞对顺铂的敏感性。在这里，我们试图评估BAD凋亡途径的激酶和磷酸酶成分如何影响OVCA的化学敏感性。采用免疫荧光法检测64例原发性晚期浆液性OVCA患者样本中细胞周期蛋白依赖性激酶1 （CDK1）和蛋白磷酸酶2C （PP2C）的蛋白水平。同时，通过Western blot分析，对母/子对铂敏感/耐药的OVCA细胞系（A2008/C13, A2780S/A2780CP, Chi/ChiR）中camp依赖性蛋白激酶（PKA）、AKT和PP2C的水平进行定量分析。用siRNA转染BAD通路激酶CDK1，观察对BAD磷酸化和顺铂诱导的细胞凋亡的影响。对原发性铂类药物治疗完全缓解的OVCA患者样本显示，CDK1蛋白水平比完全缓解的样本高4倍（p<0.0001）， PP2C蛋白水平低2倍（p=0.14）。与铂敏感的OVCA细胞系亚克隆相比，铂抗性的PP2C蛋白水平较低。所有抗铂的OVCA细胞系亚克隆的PKA水平均高于铂敏感的OVCA细胞系亚克隆。选择性siRNA缺失CDK1增加对顺铂诱导的细胞凋亡的敏感性（p<0.002）。BAD通路激酶和磷酸酶，包括CDK1和PP2C，与OVCA对铂的敏感性相关，可能代表着提高细胞毒性疗效的治疗机会。
The BCL2 family proteins are critical mediators of cellular apoptosis and, as such, have been implicated as determinants of cancer cell chemo-sensitivity. Recently, it has been demonstrated that the phosphorylation status of the BCL2 antagonist of cell death (BAD) protein may influence ovarian cancer (OVCA) cell sensitivity to cisplatin. Here, we sought to evaluate how kinase and phosphatase components of the BAD apoptosis pathway influence OVCA chemo-sensitivity. Protein levels of cyclin-dependent kinase 1 (CDK1) and protein phosphatase 2C (PP2C) were measured by immunofluorescence in a series of 64 primary advanced-stage serous OVCA patient samples. In parallel, levels of cAMP-dependent protein kinase (PKA), AKT, and PP2C were quantified by Western blot analysis in paired mother/daughter platinum-sensitive/resistant OVCA cell lines (A2008/C13, A2780S/A2780CP, Chi/ChiR). BAD pathway kinase CDK1 was depleted using siRNA transfection, and the influence on BAD phosphorylation and cisplatin-induced apoptosis was evaluated. OVCA patient samples that demonstrated complete responses to primary platinum-based therapy demonstrated 4-fold higher CDK1 (p<0.0001) and 2-fold lower PP2C (p=0.14) protein levels than samples that demonstrated incomplete responses. Protein levels of PP2C were lower in the platinum-resistant versus that shown in the platinum-sensitive OVCA cell line sub-clones. Levels of PKA were higher in all platinum-resistant than in platinum-sensitive OVCA cell line sub-clones. Selective siRNA depletion of CDK1 increased sensitivity to cisplatin-induced apoptosis (p<0.002). BAD pathway kinases and phosphatases, including CDK1 and PP2C, are associated with OVCA sensitivity to platinum and may represent therapeutic opportunities to enhance cytotoxic efficacy.
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影响因子：
4.1
作者：
Lizcano, JM;Morrice, N;Cohen, P
通讯作者：
Cohen, P
影响因子：
2.5
作者：
Yang, L;Omori, K;Inagaki, C
通讯作者：
Inagaki, C
DOI：
10.1073/pnas.89.7.3070
发表时间：
1992-04-01
影响因子：
11.1
作者：
GODWIN, AK;MEISTER, A;ANDERSON, ME
通讯作者：
ANDERSON, ME
DOI：
10.1158/1078-0432.ccr-11-0735
发表时间：
2011-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Marchion DC;Cottrill HM;Xiong Y;Chen N;Bicaku E;Fulp WJ;Bansal N;Chon HS;Stickles XB;Kamath SG;Hakam A;Li L;Su D;Moreno C;Judson PL;Berchuck A;Wenham RM;Apte SM;Gonzalez-Bosquet J;Bloom GC;Eschrich SA;Sebti S;Chen DT;Lancaster JM
通讯作者：
Lancaster JM
影响因子：
64.5
作者：
YANG, E;ZHA, JP;KORSMEYER, SJ
通讯作者：
KORSMEYER, SJ