ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation.

Mei-Chun Chen,Ling-Ming Tseng,Chih-Yi Hsu,Hsin-Chen Lee,Sheng-Fan Wang,Li-Lin Hsu

doi:10.3390/cells9071598

Mei-Chun Chen, Ling-Ming Tseng + Show 4 more

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https://doi.org/10.3390/cells9071598

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Abstract

xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.

Highlights

Breast cancer is the most common malignancy and the leading cause of cancer death in women [1]. developments of antiestrogen and trastuzumab therapy (Herceptin) have benefited breast cancer patients, metastasis and recurrent cases still affectCells 2020, 9, 1598; doi:10.3390/cells9071598 www.mdpi.com/journal/cellsCells 2020, 9, 1598 patient survival, in particular for patients with triple-negative breast cancer (TNBC) [2,3]
We first compared the expression of xCT in four breast cancer cell lines, MCF-7, MDA-MB-231, Hs-578t, and HCC-1937, and we found that MDA-MB-231, Hs-578t, and HCC1937 cells had higher gene and protein expressions of xCT than MCF-7 cells (Figure 1A,B)
To evaluate whether the energy sensor AMPK is involved in the glucose-deprivation-induced cell death of the breast cancer cells, we examined the effect of glucose deprivation on the AMPK

Summary

Introduction

Developments of antiestrogen (tamoxifen and aromatase inhibitors) and trastuzumab therapy (Herceptin) have benefited breast cancer patients, metastasis and recurrent cases still affect. Cells 2020, 9, 1598 patient survival, in particular for patients with triple-negative breast cancer (TNBC) [2,3]. More targeted, less toxic therapies for breast cancer are urgently needed. Cancer cell proliferation requires excess nutrients compared with bioenergetics needs and shunts metabolites into pathways that support biosynthesis [4,5]. The deregulated cellular energetics and metabolic reprogramming were identified as cancer hallmarks [6]. The metabolic alterations were demonstrated in certain subtypes of breast cancer, such as TNBC [7]. Understanding the metabolism of cancer cells is helpful for the development of anticancer therapies

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