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Metformin reverses multidrug resistance and epithelial–mesenchymal transition (EMT) via activating AMP-activated protein kinase (AMPK) in human breast cancer cells

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Abstract

Breast cancer is the most frequently diagnosed tumor type and the primary leading cause of cancer deaths in women worldwide and multidrug resistance is the major obstacle for breast cancer treatment improvement. Emerging evidence suggests that metformin, the most widely used antidiabetic drug, resensitizes and cooperates with some anticancer drugs to exert anticancer effect. However, there are no data regarding the reversal effect of metformin on chemoresistance in breast cancer. In the present study, we investigated the resistance reversal effect of metformin on acquired multidrug-resistant breast cancer cells MCF-7/5-Fu derived from MCF-7 breast cancer cells and innate multidrug-resistant MDA-MB-231 breast cancer cells, and we found that metformin resensitized MCF7/5-FU and MDA-MB-231 to 5-fluorouracil (5-FU), adriamycin, and paclitaxel. We also observed that metformin reversed epithelial–mesenchymal transition (EMT) phenotype and decreased the invasive capacity of MCF7/5-FU and MDA-MB-231 cells. However, there were no significant changes upon metformin-treated MCF7 cells. Moreover, we found metformin treatment activated AMPK signal pathway in MCF7/5-FU and MDA-MB-231 cells and compound C, the AMPK inhibitor, could partly abolish the resensitization and EMT reversal effect of metformin. To the best of our knowledge, we are the first to report that metformin can resensitize multidrug-resistant breast cancer cells due to activating AMPK signal pathway. Our study will help elucidate the mechanism of chemoresistance and establish new strategies of chemotherapy for human breast cancer.

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Acknowledgments

This study was supported by Grants from the National Natural Science Foundation of China (81272450).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Hengzhigang Road 78#, Guangzhou, 510095, Guangdong, People’s Republic of China

    Chen Qu, Weijia Zhang, Guopei Zheng, Zijuan Zhang, Jiang Yin & Zhimin He

  2. Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, People’s Republic of China

    Chen Qu

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  1. Chen Qu
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  2. Weijia Zhang
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  4. Zijuan Zhang
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Correspondence to Zhimin He.

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Chen Qu and Weijia Zhang have contributed equally to the work.

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Qu, C., Zhang, W., Zheng, G. et al. Metformin reverses multidrug resistance and epithelial–mesenchymal transition (EMT) via activating AMP-activated protein kinase (AMPK) in human breast cancer cells. Mol Cell Biochem 386, 63–71 (2014). https://doi.org/10.1007/s11010-013-1845-x

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