title: Dichloroacetate potentiates tamoxifen-induced cell death in breast cancer cells via downregulation of the epidermal growth factor receptor.
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.
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: Sang Hyeok
authors: SH
authors: Woo
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: Sung-Keum
authors: SK
authors: Seo
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.|School of Life Science and Biotechnology, Korea University, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors: Yoonhwa
authors: Y
authors: Park
authors: Department of Surgery, Breast Cancer Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, 13620, Republic of Korea.
authors: Eun-Kyu
authors: EK
authors: Kim
authors: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: Min-Ki
authors: MK
authors: Seong
authors: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: Hyun-Ah
authors: HA
authors: Kim
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: Jie-Young
authors: JY
authors: Song
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: Sang-Gu
authors: SG
authors: Hwang
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: Jin Kyung
authors: JK
authors: Lee
authors: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: Woo Chul
authors: WC
authors: Noh
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea.
authors: In-Chul
authors: IC
authors: Park
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D013629:Tamoxifen; D003999:Dichloroacetic Acid; C512478:EGFR protein, human; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases
keywords: breast cancer; dichloroacetate; epidermal growth factor receptor; pyruvate dehydrogenase kinase; tamoxifen