期刊
ONCOTARGET
卷 7, 期 30, 页码 48501-48516出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10363
关键词
gemcitabine; breast cancer; autophagy; estrogen receptor; P62
资金
- National Program on Key Basic Research Project [2014CB542101]
- National Natural Science Foundation of China [81373115]
- Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents and for Innovative Research Team in Zhejiang Provinc [2010R50046]
Several clinical trials revealed that estrogen receptor (ER) status had relevance to the response of mammary malignancy to chemotherapy. Autophagy has emerged as an important cellular mechanism of tumor cells in response to anticancer therapy. The aim of this study is to investigate whether gemcitabine induces autophagy, and more importantly, whether such autophagy is functional relevant to the therapeutic effects of gemcitabine in breast cancer cells in relation to the ER status. In our study, autophagy was induced both in ER+ MCF-7 and ER- MDA-MB-231 cells by gemcitabine markedly, while the autophagy plays distinct roles - cytoprotective in ER- MDA-MB-231 and cytotoxic in ER+ MCF-7 cells. Gemcitabine treatment leads to the activation of ER alpha-ERK-P62 signal pathway in MCF-7 cells which may augment the autophagic degradation, thus results in the excessive activation of autophagy and irreversible autophagic cell death eventually. Inhibition of ER alpha-ERK-P62 cascades in MCF-7 cells by small interfering RNA or PD98059 impairs the autophagic degradation, and leads to autophagic switch - from cytotoxic autophagy to cytoprotection. Moreover, stable overexpression of ER alpha in the ER- BCap37 breast cancer cell line enhances the gemcitabine-induced autophagy flux and switches the autophagic cytoprotection in ER- BCap37 to cytotoxicity effect in ER+ BCap37 cells. Our study firstly demonstrated that ER status influences gemcitabine efficacy via modulating the autophagy in breast cancer cells.
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