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AMPK Pathway Activation Improves the Sensitivity of Triple-Negative Breast Cancer Cells to Adriamycin
Vol 37, Issue 3, 2023
Abstract
Objectives: As the worst and most aggressive prognostic subtype of clinical breast cancer, triple-negative breast cancer (TNBC) accounts for 25% of total breast cancer (BC) deaths. This study aims to explore the relationship between Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathway activity and adriamycin (ADM) resistance in TNBC. Methods: MDA-MB-231 cells (a TNBC cell line) were treated with ADM to obtain ADM-resistant MDA-MB-231 (MDA-MB-231/ADM) cells. MDA-MB-231/ADM cells treated with A-769662 (an activator of AMPK) and Compound C (an inhibitor of AMPK) were set as the A-769662 and Compound C groups, respectively. Western blot was utilized to detect the AMPK pathway-related protein expression in TNBC tissues and MDA-MB-231 cells. Cell function assays [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry and colony formation assay] were employed for investigating the roles of A-769662 and Compound C in ADM resistance, apoptosis, and colony formation of MDA-MB-231/ADM cells and MDA-MB-231 cells. Results: In this study, AMPK pathway activity was inhibited in TNBC tissues. In addition, AMPK pathway activity exhibited a significant decrease in MDA-MB-231/ADM cells and ADM-resistance TNBC tissues compared with the corresponding ADM-sensitive TNBC tissues and MDA-MB-231 cells, respectively. After ADM treatment, the AMPK pathway activation in MDA-MB-231/ADM cells induced by A-769662 significantly reduced the half-maximal inhibitory concentration (IC50) and colony formation ability of ADM while increasing the apoptosis rate. Nevertheless, inhibiting the AMPK signaling pathway using Compound C notably increased the IC50 of ADM and colony formation ability and reduced the apoptosis of cells. Conclusions: After the treatment with ADM, the activation of the AMPK pathway greatly enhanced the MDA-MB-231/ADM cells’ sensitivity to ADM, promoted apoptosis, and inhibited cell growth. Furthermore, the activation of AMPK signaling may be an important strategy to inhibit ADM resistance in TNBC.
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy