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Abstract

Metabolic reprogramming in cancer cells has recently been recognized as an essential hallmark of neoplasia. In this context, metabolic alterations represent an attractive therapeutic target, and encouraging results with drugs targeting various metabolic processes have been obtained in preclinical studies. Recently, several studies have suggested that dichloroacetate (DCA), a specific pyruvate dehydrogenase kinase inhibitor, may be a potential anticancer drug in a large number of diverse tumors. However, the precise mechanism is not fully understood, which is important for the use of DCA in cancer treatment. In the present study, we found that DCA sensitized MCF7 breast cancer cells to tamoxifen-induced cell death by decreasing epidermal growth factor receptor (EGFR) expression. The downregulation of EGFR was caused by degradation of the protein. Furthermore, p38 mitogen-activated protein kinase played an important role in DCA/tamoxifen-induced EGFR degradation. Finally, DCA also promoted comparable tamoxifen-induced cell death in tamoxifen-resistant MCF7 cells, which were established by long-term treatment with tamoxifen. In summary, our results suggest that DCA is an attractive potential drug that sensitizes cells to tamoxifen-induced cell death and overcome tamoxifen resistance via downregulation of EGFR expression in breast cancer cells. 

Author information

Woo SH1, Seo SK1, Park Y1,2, Kim EK3, Seong MK4, Kim HA4, Song JY1, Hwang SG1, Lee JK5, Noh WC4, Park IC1.​

1Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.

2School of Life Science and Biotechnology, Korea University, Seongbuk-gu, Seoul, 02841, Republic of Korea.

3Department of Surgery, Breast Cancer Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, 13620, Republic of Korea.

4Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.

5KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.