Glucose regulated protein 78 (GRP78) inhibits apoptosis and attentinutes chemosensitivity of gemcitabine in breast cancer cell via AKT/mitochondrial apoptotic pathway

The underlying mechanism of gemcitabine resistance during breast cancer treatment remains unclear. Glucose regulated protein 78 (GRP78) frequently triggered by anticancer agents, was substantially elevated in gemcitabine resistant sublines. Ectopic expression of GRP78 changes gemcitabine chemosensit...

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Published in:Biochemical and biophysical research communications 2016-06, Vol.474 (3), p.612-619
Main Authors: Xie, Jie, Tao, Zhong-Hua, Zhao, Jiang, Li, Ting, Wu, Zheng-Hua, Zhang, Jin-Feng, Zhang, Jian, Hu, Xi-Chun
Format: Article
Language:English
Subjects:
Antimetabolites, Antineoplastic - administration & dosage
Apoptosis
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Deoxycytidine - administration & dosage
Deoxycytidine - analogs & derivatives
Dose-Response Relationship, Drug
Gemcitabine resistance
GRP78
Heat-Shock Proteins - metabolism
Humans
MCF-7 Cells
Mitochondria - drug effects
Mitochondria - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction - drug effects
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Summary:The underlying mechanism of gemcitabine resistance during breast cancer treatment remains unclear. Glucose regulated protein 78 (GRP78) frequently triggered by anticancer agents, was substantially elevated in gemcitabine resistant sublines. Ectopic expression of GRP78 changes gemcitabine chemosensitivity and apoptosis levels in breast cancer cells. Further experiments showed an involvement of caspase 9, not caspase 8, in gemcitabine resistance and GRP78-mediated chemosensitivity, suggesting that mitochondria apoptotic pathway was activated by GRP78. This finding was further supported by the observations of AKT activation, Bcl-2 increase, Bax and Bim decrease. Conclusively, GRP78 plays a vital role in gemcitabine resistance and clinical strategy to improve gemcitabine efficacy in breast cancer by manipulating GRP78 should be explored. •GRP78 change gemcitabine chemosensitivity and apoptosis by activating Akt/mitochondria apoptotic pathway.•Ectopic expressions of GRP78 change gemcitabine chemosensitivity and apoptosis.•Akt/mitochondria apoptotic pathway, rather than ER stress-induced ER-Ca2+-caspase 8 pathway was activated by GRP78.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2016.03.002