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 March 1, 2019; First 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 1

Chronic stress promotes ADRB2-dependent cancer stem cell–like properties in vivo.

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Chronic stress promotes ADRB2-dependent cancer stem cell–like properties...
(A) Tumor growth of MDA-MB-231 tumors in control (Ctrl) and stressed mice; n = 5 (1-way ANOVA). (B–D) Primary MDA-MB-231 tumors from the Ctrl and stress groups were subjected to immunoblot (C, control; S, stressed) (B), immunohistochemical staining (scale bar: 50 μm; original magnification, ×20, ×40, ×96 [insets]) (C), and primary and secondary spheroid formation; n = 5 (1-way ANOVA) (D). (E) Concentrations (pg/ml) of cortisol (Cort), norepinephrine (NE), and epinephrine (Epi) in serum of Ctrl and stress mice after the last day of stress; n = 5 (Student’s t test). (F) Immunoblot analysis of indicated antibodies in MDA-MB-231 cells treated with indicated concentrations of Epi. (G) Growth of Ctrl, propranolol (Pro), stress, and stress-induced propranolol-treated (Pro + stress) MDA-MB-231 tumors in mice; n = 6 (1-way ANOVA). (H) MDA-MB-231 cells were transfected with siADRB2 and then treated with Epi for 5 days. Expression of proteins was determined by immunoblot analysis. (I) Growth of MDA-MB-231 tumors in Ctrl and stress mice in the presence or absence of ICI118,551 (ICI); n = 5 (1-way ANOVA). (J) Model of chronic stress–mediated cancer stem-like traits mediated by β2-adrenergic receptor (ADRB2) signaling. Data are representative of at least 3 independent experiments. Data represent mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001.