Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells
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
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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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 5

LDHA generating lactate enhances the USP28 signaling.

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LDHA generating lactate enhances the USP28 signaling. (A) Immunoblots of...
(A) Immunoblots of siNC and siLDHA MDA-MB-231 cells treated with CHX for the indicated times. Intensity of USP28 expression for each time point was quantified by densitometry and plotted against time (right panel). (B) Immunoblots of MCF-7 cells treated for 5 days with Epi and/or siLDHA followed by incubation with or without MG132 for 6 hours. (C) Ubiquitin assays of 293T cells transfected with ubiquitin (Ubi) and siLDHA followed by treatment with Epi. (D) Immunoblots of MDA-MB-231 cells treated with the indicated concentrations of sodium oxamate (Oxa) for 48 hours. (E) Immunoblots of MDA-MB-231 and MCF-7 cells treated with lactate (Lac) for 72 hours. (F) Immunoblots of MDA-MB-231 cells transfected with USP28 WT or C171A and then treated with lactate for 72 hours. (G) Immunoblots of immunoprecipitation experiments of 293T cells transfected with USP28 WT or C171A and then treated with lactate for 72 hours. (H) MDA-MB-231 cells were treated with lactate, hydrochloric acid (HCl), and acetic acid (HAC) for 72 hours. Expression of the indicated proteins was examined by immunoblotting. (I) Snapshot structures of USP28 interacting with MYC motif extracted from constant-pH MD simulations at 2 representative pH conditions. Gray cartoons, USP28; green cartoons, MYC; blue spheres, Lys51 and Lys52 on MYC motif; red spheres and yellow spheres, His600 and Cys171 of USP28, respectively. (J) Lactate levels in serum of Ctrl (n = 15) or stress (n = 20) mice (Student’s t test). (K) Model of chronic stress–mediated USP28 stabilization through decreased pH caused by LDHA generating lactate. Data are representative of at least 3 independent experiments. Data represent mean ± SEM; ***P < 0.001.