title: Integrative bioinformatics and proteomics-based discovery of an eEF2K inhibitor (cefatrizine) with ER stress modulation in breast cancer cells.
abstract: Eukaryotic elongation factor-2 kinase (eEF2K), a unique calcium/calmodulin-dependent protein kinase, is well known to regulate apoptosis, autophagy and ER stress in many types of human cancers. Therefore, eEF2K would be regarded as a promising therapeutic target; however, the eEF2K-regulated mechanism and its targeted inhibitor still remain to be discovered in cancer. Herein, we constructed a protein-protein interaction (PPI) network of eEF2K and achieved an eEF2K-regulated ER stress subnetwork by bioinformatics prediction. Then, we found that the differential protein expressions involved in ER stress in the context of si-eEF2K-treated MCF-7 and MDA-MB-436 cells by iTRAQ-based analyses, respectively. Integrated into these aforementioned results, we constructed a core eEF2K-regulated ER stress subnetwork in breast cancer cells. Subsequently, we screened a series of candidate compounds targeting eEF2K and discovered a novel eEF2K inhibitor (cefatrizine) with an anti-proliferative activity toward breast cancer cells. Moreover, we found that cefatrizine induced ER stress in both MCF-7 and MDA-MB-436 cells. Interestingly, we demonstrated that the mechanism of cefatrizine-induced ER stress was in good agreement with our bioinformatics and proteomics-based results. In conclusion, these results demonstrate that a novel eEF2K inhibitor (cefatrizine) induces ER stress in breast cancer cells by integrating bioinformatics prediction, proteomics analyses and experimental validation, which would provide a clue for exploring more mechanisms of eEF2K and its targeted inhibitors in cancer therapy.
authors.affiliation: Department of Neurosurgery, No. 150 Central Hospital of PLA, Luoyang, Henan 471031, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yao
authors.forename: Juntang
authors.initials: J
authors.lastname: Li
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Liu
authors.forename: Lu
authors.initials: L
authors.lastname: Zheng
authors.forename: Naijun
authors.initials: N
authors.lastname: Fan
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Jia
authors.forename: Jingjing
authors.initials: J
authors.lastname: Lv
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Zhu
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Du
authors.forename: Ci
authors.initials: C
authors.lastname: Lv
authors.forename: Feng
authors.initials: F
authors.lastname: Xie
authors.forename: Yigang
authors.initials: Y
authors.lastname: Liu
authors.forename: Xingke
authors.initials: X
authors.lastname: Wang
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fei
authors.forename: Chunfang
authors.initials: C
authors.lastname: Gao
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D002436:Cefatrizine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology / Q000379:methods*; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D040901:Proteomics / Q000379:methods*
chemical_list: D047428:Protein Kinase Inhibitors; D002436:Cefatrizine; C517689:EEF2K protein, human; D054736:Elongation Factor 2 Kinase