Inhibition of ERα/ERK/P62 cascades induces “autophagic switch” in the estrogen receptor-positive breast cancer cells exposed to gemcitabine
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Peng Shen1,*, Ming Chen1,*, Mengye He2, Luoquan Chen2, Yinjing Song2, Peng Xiao2, Xiaopeng Wan2, Feng Dai2, Ting Pan2, Qingqing Wang2
1Department of Medical Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, PR China
2Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, PR China
*These authors have contributed equally to this work
Peng Shen, email: [email protected]
Qingqing Wang, email: [email protected]
Keywords: gemcitabine, breast cancer, autophagy, estrogen receptor, P62
Received: July 03, 2015 Accepted: June 04, 2016 Published: July 1, 2016
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 ERα-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 ERα-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 ERα 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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