Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells
Bai Cui, … , Keith W. Kelley, Quentin Liu
Bai Cui, … , Keith W. Kelley, Quentin Liu
Published January 28, 2019
Citation Information: J Clin Invest. 2019;129(3):1030-1046. https://doi.org/10.1172/JCI121685.
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Research Article Metabolism Oncology

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

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Figure 2

Chronic stress–induced MYC activates SLUG transcription to stimulate CSCs.

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Chronic stress–induced MYC activates SLUG transcription to stimulate CSC...
(A) A cluster heatmap of expression profiles of mRNAs in PBS- and Epi-treated MDA-MB-231–derived tumors; n = 3. (B) Comparison of array data (fold change >2, Q < 0.05, 54 genes) with stem-like cell genes (405 genes). Common genes were verified by Epi treatment and are listed in the column according to fold change. n = 3. (C) Distribution patterns and number (d > 50 μm) of mammospheres from the negative control (shNC) or shSLUG MDA-MB-231 cells after treatment with PBS or Epi for 5 days; n = 3 (1-way ANOVA). (D) Growth of shNC or shSLUG-3 MDA-MB-231 tumors in mice with or without stress treatment; n = 6 (1-way ANOVA). (E) Dual-luciferase reporter assays of MDA-MB-231 cells transfected with SLUG truncated promoters or empty vector (EV) in the presence or absence of Epi for 5 days; n = 3 (1-way ANOVA). (F) Dual-luciferase analysis in shNC or shMYC MDA-MB-231 cells treated with PBS or Epi for 5 days and transfected with EV or SLUG promoter (–496 to 0); n = 3 (1-way ANOVA). (G) Dual-luciferase reporter assays of MDA-MB-231 cells treated with Epi for 5 days and transfected with SLUG WT, mutant 1 (Mut1, –57 to –54), mutant 2 (Mut2, –104 to –101), or mutant 3 (Mut3, –412 to –408) promoters; n = 3 (1-way ANOVA). (H) ChIP-PCR analysis in MDA-MB-231 cells of MYC occupancy on the SLUG promoter. (I) Model of Epi-induced cancer stem-like traits through MYC/SLUG signaling. Data are representative of at least 3 independent experiments. Data represent mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001.