LINCS gene expression signatures analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targeting eIF4G1
LINCS gene expression signatures analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targeting eIF4G1
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LINCS 基因表达特征分析显示博舒替尼通过靶向 eIF4G1 作为乳腺癌细胞的放射增敏剂
DOI：
10.1101/2020.04.24.059378
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发表时间：
2020-04
影响因子：
5.4
通讯作者：
HUA GUAN
中科院分区：
文献类型：
--
作者：
SAI HU;DAFEI XIE;PINGKUN ZHOU;XIAODAN LIU;XIAOYAO YIN;BO HUANG;HUA GUAN
放射抵抗是放射治疗失败和疾病进展的主要原因，导致乳腺癌死亡率增加。本研究通过对整合网络细胞标记库(LINCS)和基因表达总表(GEO)的基因表达特征分析，系统地从已知药物中筛选出潜在的候选放射增敏剂。通过浓缩分数来衡量辐射后eIF4G1沉默的乳腺癌细胞和已知药物之间整合基因表达特征的相似性。筛选出富集积分阳性的药物作为潜在的放射增敏剂。用CCK-8比色法和电离辐射后集落形成能力分析候选放射增敏剂对乳腺癌细胞(MCF-7、MX-1和MDA-MB-231)的放射增敏作用。流式细胞仪检测细胞凋亡率。Western印迹分析eIF4G1和一系列DNA损伤反应蛋白的表达。博苏替尼被认为是一种很有前途的放射增敏剂，因为它的给药显着减少了药物和电离辐射的剂量，并与较少的不良反应有关。与电离辐射或波苏替尼单独治疗相比，电离辐射和博苏替尼联合治疗显著提高了所有三种细胞系的细胞杀伤力。在三种细胞系中，MX-1细胞对电离辐射和波苏替尼最敏感。波苏替尼以剂量依赖的方式显著下调eIF4G1的表达，并降低DNA损伤反应蛋白(包括ATM、XRCC4、ATrip和GADD45a)的表达。此外，eIF4G1可能是波苏替尼调节电离辐射所致DNA损伤的关键靶点。综上所述，博苏替尼可能成为乳腺癌治疗的潜在候选放射增敏剂。
Radioresistance represents the predominant cause for radiotherapy failure and disease progression, resulting in increased breast cancer mortality. Through gene expression signatures analyses of Library of Integrated Network-Based Cellular Signatures (LINCS) and Gene Expression Omnibus (GEO), the present study aimed to identify potential candidate radiosensitizers from known drugs systematically. The similarity of integrated gene expression signatures between irradiated eIF4G1-silenced breast cancer cells and known drugs was measured by enrichment scores. Drugs with positive enrichment scores were selected as potential radiosensitizers. The radiosensitizing effects of the candidate radiosensitizers were analyzed in breast cancer cells (MCF-7, MX-1, and MDA-MB-231) by CCK-8 assays and colony-forming capability after exposure to ionizing radiation. Cell apoptosis was detected by flow cytometry. Expressions of eIF4G1 and a series of DNA damage response proteins were analyzed by Western blot assays. Bosutinib was proposed to be a promising radiosensitizer as its administration markedly reduced the dosages of both the drug and ionizing radiation and was associated with fewer adverse drug reactions. The combined treatment with ionizing radiation and bosutinib significantly increased the cells killing potency in all three cell lines as compared to ionizing radiation or bosutinib alone. MX-1 cells were revealed to be the most sensitive to both ionizing radiation and bosutinib among the three cell lines. Bosutinib noticeably downregulated the expression of eIF4G1 in a dose-dependent manner and also reduced the expression of DNA damage response proteins (including ATM, XRCC4, ATRIP, and GADD45a). Moreover, eIF4G1 could be a key target of bosutinib through which it regulates DNA damage induced by ionizing radiation. Thus, taken together, bosutinib may serve as a potential candidate radiosensitizer for breast cancer therapy.
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影响因子：
9
作者：
通讯作者：
--
DOI：
10.1073/pnas.041416598
发表时间：
2001-02-13
影响因子：
11.1
作者：
Peretz, S;Jensen, R;Glazer, PW
通讯作者：
Glazer, PW
影响因子：
5.7
作者：
Wie SM;Wellberg E;Karam SD;Reyland ME
通讯作者：
Reyland ME
DOI：
10.1093/bioinformatics/btq398
发表时间：
2010-09-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Suratanee A;Rebhan I;Matula P;Kumar A;Kaderali L;Rohr K;Bartenschlager R;Eils R;König R
通讯作者：
König R
影响因子：
12.8
作者：
Cortes JE;Jean Khoury H;Kantarjian H;Brümmendorf TH;Mauro MJ;Matczak E;Pavlov D;Aguiar JM;Fly KD;Dimitrov S;Leip E;Shapiro M;Lipton JH;Durand JB;Gambacorti-Passerini C
通讯作者：
Gambacorti-Passerini C