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

doi:10.1172/JCI121685

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 LuoJie 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

Research output: Contribution to journal › Article › peer-review

202 Scopus citations

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.

Original language	English
Pages (from-to)	1030-1046
Number of pages	17
Journal	Journal of Clinical Investigation
Volume	129
Issue number	3
DOIs	https://doi.org/10.1172/JCI121685
State	Published - Mar 2019

Bibliographical note

Publisher Copyright:
2019 © American Society for Clinical Investigation. All Rights Reserved.

Funding

This research work was supported by the National Natural Science Foundation of China (81820108024 to QL;81630005 to QL; 81573025 to QL; and 81703091 to FA); the Science and Technology Planning Project of Guangzhou (201604020163 to QL); and the Dalian High-level Talent Innovation Program (2016RD12 to QL). EWFL\u2019s work is supported by the Medical Research Council (MRC) (MR/N012097/1); Cancer Research UK (CRUK) (C37/A12011; C37/ A18784); Breast Cancer Now (2012MayPR070; 2012NovPhD016); the CRUK Imperial Centre, Imperial Experimental Cancer Medicine Centre (ECMC); and the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC).

Funders	Funder number
Medical Research Council Canada
Breast Cancer Now
NIHR Imperial Biomedical Research Centre
National Institute for Health Research Health Protection Research Unit
UK Industrial Decarbonization Research and Innovation Centre
Dalian High-level Talent Innovation Program	2016RD12
Dalian High-level Talent Innovation Program
Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre	C37/A12011, C37/ A18784, A18784
Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre
Breast Cancer Now	2012NovPhD016, 2012MayPR070
Breast Cancer Now
National Natural Science Foundation of China (NSFC)	81630005, 81820108024, 81573025, 81703091
National Natural Science Foundation of China (NSFC)
Medical Research Council-São Paulo Research Foundation	MR/N012097/1
Medical Research Council-São Paulo Research Foundation
Guangzhou Municipal Science and Technology Project	201604020163
Guangzhou Municipal Science and Technology Project

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/JCI121685

Cite this

Cui, B., Luo, Y., Tian, P., Peng, F., Lu, J., Yang, Y., Su, Q., Liu, B., Yu, J., Luo, X., Yin, L., Cheng, W., An, F., He, B., Liang, D., Wu, S., Chu, P., Song, L., Liu, X., ... Liu, Q. (2019). Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells. Journal of Clinical Investigation, 129(3), 1030-1046. https://doi.org/10.1172/JCI121685

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title = "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.",

author = "Bai Cui and Yuanyuan Luo and Pengfei Tian and Fei Peng and Jinxin Lu and Yongliang Yang and Qitong Su and Bing Liu and Jiachuan Yu and Xi Luo and Liu Yin and Wei Cheng and Fan An and Bin He and Dapeng Liang and Sijin Wu and Peng Chu and Luyao Song and Xinyu Liu and Huandong Luo and Jie Xu and Yujia Pan and Yang Wang and Dangsheng Li and Peng Huang and Qingkai Yang and Lingqiang Zhang and Zhou, \{Binhua P.\} and Suling Liu and Guowang Xu and Lam, \{Eric W.F.\} and Kelley, \{Keith W.\} and Quentin Liu",

year = "2019",

month = mar,

doi = "10.1172/JCI121685",

language = "English",

volume = "129",

pages = "1030--1046",

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Cui, B, Luo, Y, Tian, P, Peng, F, Lu, J, Yang, Y, Su, Q, Liu, B, Yu, J, Luo, X, Yin, L, Cheng, W, An, F, He, B, Liang, D, Wu, S, Chu, P, Song, L, Liu, X, Luo, H, Xu, J, Pan, Y, Wang, Y, Li, D, Huang, P, Yang, Q, Zhang, L, Zhou, BP, Liu, S, Xu, G, Lam, EWF, Kelley, KW & Liu, Q 2019, 'Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells', Journal of Clinical Investigation, vol. 129, no. 3, pp. 1030-1046. https://doi.org/10.1172/JCI121685

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AU - Cui, Bai

AU - Luo, Yuanyuan

AU - Tian, Pengfei

AU - Peng, Fei

AU - Lu, Jinxin

AU - Yang, Yongliang

AU - Su, Qitong

AU - Liu, Bing

AU - Yu, Jiachuan

AU - Luo, Xi

AU - Yin, Liu

AU - Cheng, Wei

AU - An, Fan

AU - He, Bin

AU - Liang, Dapeng

AU - Wu, Sijin

AU - Chu, Peng

AU - Song, Luyao

AU - Liu, Xinyu

AU - Luo, Huandong

AU - Xu, Jie

AU - Pan, Yujia

AU - Wang, Yang

AU - Li, Dangsheng

AU - Huang, Peng

AU - Yang, Qingkai

AU - Zhang, Lingqiang

AU - Zhou, Binhua P.

AU - Liu, Suling

AU - Xu, Guowang

AU - Lam, Eric W.F.

AU - Kelley, Keith W.

AU - Liu, Quentin

PY - 2019/3

Y1 - 2019/3

N2 - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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