Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells.

Abstract

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.

• Authors: Bai Cui, Yuanyuan Luo, Pengfei Tian, Fei Peng, Jinxin Lu, Yongliang Yang, Qitong Su, Bing Liu, Jiachuan Yu, Xi Luo, Liu Yin, Wei Cheng, Fan An, Bin He, Dapeng Liang, Sijin Wu, Peng Chu, Luyao Song, Xinyu Liu, Huandong Luo, Jie Xu, Yujia Pan, Yang Wang, Dangsheng Li, Peng Huang, Qingkai Yang, Lingqiang Zhang, Binhua P Zhou, Suling Liu, Guowang Xu, Eric W-F Lam, Keith W Kelley, Quentin Liu
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 129 Issue 3 Pg. 1030-1046 (03 01 2019) ISSN: 1558-8238 [Electronic] United States
• PMID: 30688660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MYC protein, human
• Proto-Oncogene Proteins c-myc
• SNAI1 protein, human
• Snail Family Transcription Factors
• L-Lactate Dehydrogenase
• LDHA protein, human
• Ascorbic Acid
• Epinephrine

Topics

• Animals
• Ascorbic Acid (pharmacology)
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Epinephrine (metabolism)
• Female
• Humans
• L-Lactate Dehydrogenase (metabolism)
• MCF-7 Cells
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplastic Stem Cells (enzymology, pathology)
• Proto-Oncogene Proteins c-myc (metabolism)
• Snail Family Transcription Factors (metabolism)
• Stress, Psychological (drug therapy, metabolism, pathology)