Inhibiting ROS-TFE3-dependent autophagy enhances the therapeutic response to metformin in breast cancer

Autophagy modulation is a potential therapeutic strategy for breast cancer, and a previous study indicated that metformin exhibits significant anti-carcinogenic activity. However, the ability of metformin to induce autophagy and its role in breast cancer cell death remains unclear. In this study, we...

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Published in:Free radical research 2018-08, Vol.52 (8), p.872-886
Main Authors: Tan, Miduo, Wu, Anshang, Liao, Ni, Liu, Min, Guo, Qiong, Yi, Jiansheng, Wang, Taoli, Huang, Yan, Qiu, Bo, Zhou, Wei
Format: Article
Language:English
Subjects:
Apoptosis
Autophagy
Autophagy - drug effects
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Cell Line, Tumor
Female
Humans
MCF-7 Cells
metformin
Metformin - pharmacology
Metformin - therapeutic use
Reactive Oxygen Species
TFE3
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Summary:Autophagy modulation is a potential therapeutic strategy for breast cancer, and a previous study indicated that metformin exhibits significant anti-carcinogenic activity. However, the ability of metformin to induce autophagy and its role in breast cancer cell death remains unclear. In this study, we exposed MCF-7 cells to different concentrations of metformin (2.5, 5, and 10 mM) for 48 h, and metformin-induced significant apoptosis in the MCF-7 cells. The expression levels of CL-PARP (poly(ADP-ribose) polymerase 1) and the ratio of BAX to BCL-2 were significantly increased. In addition to apoptosis, we showed that metformin increased autophagic flux in MCF-7 cells, as evidenced by the upregulation of LC3-II and downregulation of P62/SQSTM1. Moreover, pharmacological or genetic blocking of autophagy increased metformin-induced apoptosis, indicating a cytoprotective role of autophagy in metformin-treated MCF-7 cells. Mechanistically, metformin-induced TFE3 (Ser321) dephosphorylation activated TFE3 nuclear translocation and increased of TFE3 reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes and, subsequently, initiated autophagy in MCF-7 cells. Importantly, we found that metformin triggered the generation of reactive oxygen species (ROS) in MCF-7 cells. Furthermore, N-acetyl-l-cysteine (NAC), a ROS scavenger, abrogated the effects of metformin on TFE3-dependent autophagy. Notably, TFE3 expression positively correlated with breast cancer development and poor prognosis in patients. Taken together, these data demonstrate that blocking ROS-TFE3-dependent autophagy to enhance the activity of metformin warrants further attention as a treatment strategy for breast cancer.
ISSN:1071-5762
1029-2470
DOI:10.1080/10715762.2018.1485075