Dichloroacetate potentiates tamoxifen-induced cell death in breast cancer cells via downregulation of the epidermal growth factor receptor.

Sang Hyeok Woo,Jie-Young Song,Hyun-Ah Kim,Jin Kyung Lee,Sang-Gu Hwang,Woo Chul Noh,Min-Ki Seong,Sung-Keum Seo,In-Chul Park,Eun-Kyu Kim,Yoonhwa Park

doi:10.18632/oncotarget.10999

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.

Highlights

Proliferating cancer cells have considerably different metabolic requirements compared to most normal differentiated cells
We reported that apoptotic cell death in breast cancer cells was caused by the loss of mitochondrial membrane potential (MMP) [14]
We tested whether loss of MMP involved in cell death induced by the co-treatment, there was no significant change in MMP between untreated and tamoxifen/DCA-treated cells (Supplementary Figure S2)

Summary

Introduction

Proliferating cancer cells have considerably different metabolic requirements compared to most normal differentiated cells. To support rapid cell growth and proliferation, cancer cells differentially alter metabolic flux compared to the surrounding tissue to provide sufficient bioenergetics and biosynthetic intermediates. Www.impactjournals.com/oncotarget this cancer-specific metabolic remodeling is reversed by dichloroacetate (DCA), a mitochondria-targeting small molecule that can penetrate most tissues after oral administration [4]. It inhibits pyruvate dehydrogenase kinase (PDK), a member of the kinase family, leading to reactivation of pyruvate dehydrogenase (PDH), a key enzyme that shifts the flux of pyruvate into the mitochondria to promote glucose oxidation instead of glycolysis [4]. DCA has recently been evaluated in several preclinical cancer trials [5], the responses of cancer cells to DCA treatment, which determine whether DCA will provide clinical benefit in cancer treatment, have not been fully elucidated

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Conclusion