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

• 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
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.03.002

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.