Preclinical evaluation of cyclin dependent kinase 11 and casein kinase 2 survival kinases as RNA interference targets for triple negative breast cancer therapy.
Preclinical evaluation of cyclin dependent kinase 11 and casein kinase 2 survival kinases as RNA interference targets for triple negative breast cancer therapy.
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DOI：
10.1186/s13058-015-0524-0
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Trembley JH
中科院分区：
文献类型：
--
作者：
Kren BT;Unger GM;Abedin MJ;Vogel RI;Henzler CM;Ahmed K;Trembley JH
需要针对侵袭性乳腺癌（如三阴性乳腺癌（TNBC））的靶向治疗。使用小干扰RNA（siRNA）来使存活基因的表达失活，提供了杀死这些癌细胞的工具。细胞周期蛋白依赖性激酶11（CDK 11）是一种生存蛋白激酶，调节RNA转录、剪接和有丝分裂。酪蛋白激酶2（CK 2）是一种抑制癌细胞死亡的生存蛋白激酶。消除这些基因的表达对乳腺癌具有潜在的治疗效用。在乳腺癌细胞系和组织阵列中检测CDK 11和CK 2 mRNA及相关蛋白的表达水平。分析乳腺癌亚型中CDC 2L 1、CDC 2L 2、CCNL 1、CCNL 2、CSNK 2A 1、CSNK 2A 2和CSNK 2B基因的RNA表达水平。通过活力和克隆存活测定以及RNA和蛋白质测量来检查针对CDK 11和CK 2的siRNA转染培养细胞后的效果。通过荧光激活的细胞分选分析TNBC细胞对替尼泊金（TBG）纳米胶囊的摄取。TBG纳米帽在携带TNBC异种移植肿瘤的小鼠中递送靶向CDK 11或CK 2的siRNA。评估转录物切割和响应参数。我们发现CDK 11和CK 2 mRNA和蛋白在大多数人乳腺癌细胞中有强表达。TNBC患者组织的免疫组织化学分析显示，与正常组织相比，100%的肿瘤对CDK 11染色呈阳性，具有高核强度。癌症基因组图谱分析将基础乳腺癌与其他乳腺癌亚型和正常乳腺进行比较，显示出统计学显着差异。CDK 11和/或CK 2在乳腺癌细胞中的下调导致细胞活力和克隆存活的显著丧失，降低相关mRNA和蛋白表达，并诱导细胞死亡变化。TBG纳米帽被培养物和异种移植肿瘤中的TNBC细胞吸收。用针对CDK 11的TBG- siRNA或针对CK 2 αα'纳米帽的TBG- siRNA处理诱导TNBC肿瘤中CDK 11和CK 2 α转录物的适当切割，并导致MDA-MB-231肿瘤缩小、增殖丧失和靶基因表达降低。CDK 11和CK 2表达对于乳腺癌细胞存活（包括TNBC）是单独必需的。这些基因作为有前途的新靶点用于乳腺癌的治疗开发。
Targeted therapies for aggressive breast cancers like triple negative breast cancer (TNBC) are needed. The use of small interfering RNAs (siRNAs) to disable expression of survival genes provides a tool for killing these cancer cells. Cyclin dependent kinase 11 (CDK11) is a survival protein kinase that regulates RNA transcription, splicing and mitosis. Casein kinase 2 (CK2) is a survival protein kinase that suppresses cancer cell death. Eliminating the expression of these genes has potential therapeutic utility for breast cancer. Expression levels of CDK11 and CK2 mRNAs and associated proteins were examined in breast cancer cell lines and tissue arrays. RNA expression levels of CDC2L1, CDC2L2, CCNL1, CCNL2, CSNK2A1, CSNK2A2, and CSNK2B genes in breast cancer subtypes were analyzed. Effects following transfection of siRNAs against CDK11 and CK2 in cultured cells were examined by viability and clonal survival assays and by RNA and protein measures. Uptake of tenfibgen (TBG) nanocapsules by TNBC cells was analyzed by fluorescence-activated cell sorting. TBG nanocapsules delivered siRNAs targeting CDK11 or CK2 in mice carrying TNBC xenograft tumors. Transcript cleavage and response parameters were evaluated. We found strong CDK11 and CK2 mRNA and protein expression in most human breast cancer cells. Immunohistochemical analysis of TNBC patient tissues showed 100% of tumors stained positive for CDK11 with high nuclear intensity compared to normal tissue. The Cancer Genome Atlas analysis comparing basal to other breast cancer subtypes and to normal breast revealed statistically significant differences. Down-regulation of CDK11 and/or CK2 in breast cancer cells caused significant loss of cell viability and clonal survival, reduced relevant mRNA and protein expression, and induced cell death changes. TBG nanocapsules were taken up by TNBC cells both in culture and in xenograft tumors. Treatment with TBG- siRNA to CDK11 or TBG- siRNA to CK2αα’ nanocapsules induced appropriate cleavage of CDK11 and CK2α transcripts in TNBC tumors, and caused MDA-MB-231 tumor reduction, loss of proliferation, and decreased expression of targeted genes. CDK11 and CK2 expression are individually essential for breast cancer cell survival, including TNBC. These genes serve as promising new targets for therapeutic development in breast cancer.
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影响因子：
8
作者：
Choi HH;Choi HK;Jung SY;Hyle J;Kim BJ;Yoon K;Cho EJ;Youn HD;Lahti JM;Qin J;Kim ST
通讯作者：
Kim ST
影响因子：
4.8
作者：
Hu, DL;Mayeda, A;Kidd, VJ
通讯作者：
Kidd, VJ
影响因子：
8.4
作者：
Giusiano, Sophie;Cachet, Claude;Charpin, Colette
通讯作者：
Charpin, Colette
影响因子：
11.5
作者：
Duan, Zhenfeng;Zhang, Jianming;Hornicek, Francis J.
通讯作者：
Hornicek, Francis J.
影响因子：
5.7
作者：
GAPANY, M;FAUST, RA;AHMED, K
通讯作者：
AHMED, K