期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 3, 页码 1030-1046出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI121685
关键词
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资金
- National Natural Science Foundation of China [81820108024, 81630005, 81573025, 81703091]
- Science and Technology Planning Project of Guangzhou [201604020163]
- Dalian High-level Talent Innovation Program [2016RD12]
- Medical Research Council (MRC) [MR/N012097/1]
- Cancer Research UK (CRUK) [C37/A12011, C37/A18784]
- Breast Cancer Now [2012MayPR070, 2012NovPhD016]
- CRUK Imperial Centre, Imperial Experimental Cancer Medicine Centre (ECMC)
- National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC)
- Medical Research Council [MR/N012097/1] Funding Source: researchfish
- MRC [MR/N012097/1] Funding Source: UKRI
Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress-induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic stress-induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.
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