Interactome Analysis of Microtubule-targeting Agents Reveals Cytotoxicity Bases in Normal Cells

作     者：Andres Julian Gutierrez-Escobar Gina Mendez-Callejas 

作者机构：Grupo de Investigaciones Biomedicas y Genetica Aplicada-GIBGAUniversidad de Ciencias Aplicadas y Ambientales U.D.C.A.Bogota 111166Colombia 

出 版 物：《Genomics, Proteomics & Bioinformatics》 (基因组蛋白质组与生物信息学报（英文版）)

年 卷 期：2017年第15卷第6期

页      面：352-360页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 1001[医学-基础医学(可授医学、理学学位)] 071009[理学-细胞生物学] 0714[理学-统计学（可授理学、经济学学位）] 0703[理学-化学] 0701[理学-数学] 0812[工学-计算机科学与技术（可授工学、理学学位）] 

基　　金：supported by COLCIENCIAS(Grant No.5992014) Colombia awarded to GM 

主　　题：Cancer treatment Microtubule-targeting agentInteractome analysis Cancer biology Apoptosis 

摘      要：Cancer causes millions of deaths annually and microtubule-targeting agents （MTAs） are the most commonly-used anti-cancer drugs. However, the high toxicity of MTAs on normal cells raises great concern. Due to the non-selectivity of MTA targets, we analyzed the interaction net- work in a non-cancerous human cell. Subnetworks of fourteen MTAs were reconstructed and the merged network was compared against a randomized network to evaluate the functional rich- ness. We found that 71.4% of the MTA interactome nodes are shared, which affects cellular pro- cesses such as apoptosis, cell differentiation, cell cycle control, stress response, and regulation of energy metabolism. Additionally, possible secondary targets were identified as client proteins of interphase microtubules. MTAs affect apoptosis signaling pathways by interacting with client pro- teins of interphase microtubules, suggesting that their primary targets are non-tumor cells. The paclitaxel and doxorubicin networks share essential topological axes, suggesting synergistic effects. This may explain the exacerbated toxicity observed when paclitaxel and doxorubicin are used in combination for cancer treatment.