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

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.

Alpha linolenic acid and oleic acid additively down-regulate malignant potential and positively cross-regulate AMPK/S6 axis in OE19 and OE33 esophageal cancer cells

“…AMPK causes cell cycle arrest in certain cancer cell lines such as hepatoma HepG2, prostate carcinoma PC-3 and breast cancer MCF-7 by up-regulating tumor suppressor genes such as p53, p21 and p27 [33][34][35]. Similar to these reports, we observed that the suppressive effect of OA and/or ALA on esophageal cancer cell proliferation was mediated by activation of AMPK and/or decreasing phosphorylation of S6.…”

Epithelial-Mesenchymal Transition and Drug Resistance: Role, Molecular Mechanisms, and Therapeutic Strategies

“…Evidence is beginning to emerge that several ABC transporters contain binding sites for EMT regulators, such as Twist, Snail, Slug, FOXC2, and E12/E47 [46], and at least 3 of these factors, Snail, Twist, and FOXC2, can modulate the promoter activity of ABC transporters. Interestingly, an activated Ras oncogene, which is a potent activator of the AMPK pathway, has been found to partly abolish resensitization and preserve EMT in MCF7/5-fluorouracil and MDA-MB-231 cells [47]. The authors of this study also discovered that the antidiabetic drug metformin had the ability to reverse MDR by inhibiting EMT.…”

Physcion inhibits the metastatic potential of human colorectal cancer SW620 cells in vitro by suppressing the transcription factor SOX2

“…However, AMPK activation by metformin inhibits the migration and invasion of melanoma cells [40] . Moreover, a recent study showed that metformin reverses EMT via the activation of AMPK in human breast cancer cells [41] . Accordingly, it seems that the role of AMPK in cell metastatic potential may be dependent on the type of stimulus or the cell that is used in the assay.…”