ER stress-mediated apoptosis induced by celastrol in cancer cells and important role of glycogen synthase kinase-3β in the signal network

被引：53

作者：

Feng, L. ^{[1
]}

Zhang, D. ^{[1
]}

Fan, C. ^{[1
]}

Ma, C. ^{[2
]}

Yang, W. ^{[3
]}

Meng, Y. ^{[1
]}

Wu, W. ^{[1
]}

Guan, S. ^{[1
]}

Jiang, B. ^{[1
]}

Yang, M. ^{[1
]}

Liu, X. ^{[1
]}

Guo, D. ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[2] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China

[3] Kunming Med Coll, Yunnan Pharmacol Labs Nat Prod, Kunming 650031, Peoples R China

来源：

CELL DEATH & DISEASE | 2013年 / 4卷

基金：

中国国家自然科学基金;

关键词：

celastrol; apoptosis; endothelium reticulum; proteomics; bioinformatics; INDUCED CASPASE-3 ACTIVATION; THUNDER GOD VINE; KINASE; 3-BETA; TOM COMPLEX; MOLECULAR TARGETS; HSP90; INHIBITOR; OUTER-MEMBRANE; IN-VIVO; MITOCHONDRIA; BAX;

D O I：

10.1038/cddis.2013.222

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

HeLa cells treated with celastrol, a natural compound with inhibitive effect on proteasome, exhibited increase in apoptotic rate and characteristics of apoptosis. To clarify the signal network activated by celastrol to induce apoptosis, both the direct target proteins and undirect target proteins of celastrol were searched in the present study. Proteasome catalytic subunit beta 1 was predicted by computational analysis to be a possible direct target of celastrol and confirmed by checking direct effect of celastrol on the activity of recombinant human proteasome subunit beta 1 in vitro. Undirect target-related proteins of celastrol were searched using proteomic studies including two-dimensional electrophoresis (2-DE) analysis and iTRAQ-based LC-MS analysis. Possible target-related proteins of celastrol such as endoplasmic reticulum protein 29 (ERP29) and mitochondrial import receptor Tom22 (TOM22) were found by 2-DE analysis of total cellular protein expression profiles. Further study showed that celastrol induced ER stress and ER stress inhibitor could ameliorate cell death induced by celastrol. Celastrol induced translocation of Bax into the mitochondria, which might be related to the upregulation of BH-3-only proteins such as BIM and the increase in the expression level of TOM22. To further search possible target-related proteins of celastrol in ER and ER-related fractions, iTRAQ-based LC-MS method was use to analyze protein expression profiles of ER/microsomal vesicles-riched fraction of cells with or without celastrol treatment. Based on possible target-related proteins found in both 2-DE analysis and iTRAQ-based LC-MS analysis, protein-protein interaction (PPI) network was established using bioinformatic analysis. The important role of glycogen synthase kinase-3 beta (GSK3 beta) in the signal cascades of celastrol was suggested. Pretreatment of LiCL, an inhibitor of GSK3 beta, could significantly ameliorate apoptosis induced by celastrol. On the basis of the results of the present study, possible signal network of celastrol activated by celastrol leading to apoptosis was predicted.

引用

页码：e715 / e715

页数：10

共 59 条

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Peptide ligand screening of α-synuclein aggregation modulators by in silico panning [J].