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Cell Metab. 2018 Jul 3;28(1):69-86.e6. doi: 10.1016/j.cmet.2018.06.006.

Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling.

Author information

1
Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: mingluo@med.umich.edu.
2
Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
3
Center of Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
4
Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242, USA.
5
Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: mwicha@med.umich.edu.

Abstract

Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.

KEYWORDS:

HIF1α; NRF2; antioxidant responses; cancer stem cell metabolism; cancer stem cell plasticity; glycolysis; hypoxia; oxidative phosphorylation

PMID:
29972798
PMCID:
PMC6037414
[Available on 2019-07-03]
DOI:
10.1016/j.cmet.2018.06.006

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