Dichloroacetate potentiates tamoxifen-induced cell death in breast cancer cells via downregulation of the epidermal growth factor receptor
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Sang Hyeok Woo1,*, Sung-Keum Seo1,*, Yoonhwa Park1,2, Eun-Kyu Kim3, Min-Ki Seong4, Hyun-Ah Kim4, Jie-Young Song1, Sang-Gu Hwang1, Jin Kyung Lee5, Woo Chul Noh4, In-Chul Park1
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
*These authors contributed equally to this work
In-Chul Park, email: [email protected]
Keywords: tamoxifen, breast cancer, dichloroacetate, epidermal growth factor receptor, pyruvate dehydrogenase kinase
Received: May 18, 2016 Accepted: July 22, 2016 Published: August 01, 2016
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.
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