Title |
Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling
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Published in |
Cell Metabolism (Science Direct), July 2018
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DOI | 10.1016/j.cmet.2018.06.006 |
Pubmed ID | |
Authors |
Ming Luo, Li Shang, Michael D. Brooks, Evelyn Jiagge, Yongyou Zhu, Johanna M. Buschhaus, Sarah Conley, Melissa A. Fath, April Davis, Elizabeth Gheordunescu, Yongfang Wang, Ramdane Harouaka, Ann Lozier, Daniel Triner, Sean McDermott, Sofia D. Merajver, Gary D. Luker, Douglas R. Spitz, Max S. Wicha |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 9 | 36% |
United Kingdom | 1 | 4% |
Brazil | 1 | 4% |
Italy | 1 | 4% |
Australia | 1 | 4% |
Indonesia | 1 | 4% |
India | 1 | 4% |
Germany | 1 | 4% |
Unknown | 9 | 36% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 13 | 52% |
Scientists | 8 | 32% |
Science communicators (journalists, bloggers, editors) | 3 | 12% |
Practitioners (doctors, other healthcare professionals) | 1 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 219 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 45 | 21% |
Researcher | 35 | 16% |
Student > Bachelor | 22 | 10% |
Student > Master | 22 | 10% |
Student > Doctoral Student | 17 | 8% |
Other | 25 | 11% |
Unknown | 53 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 76 | 35% |
Agricultural and Biological Sciences | 23 | 11% |
Medicine and Dentistry | 15 | 7% |
Engineering | 6 | 3% |
Pharmacology, Toxicology and Pharmaceutical Science | 5 | 2% |
Other | 26 | 12% |
Unknown | 68 | 31% |