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

Bai Cui,Quentin Liu,Peng Chu,Xi Luo,Bin He,Jie Xu,Pengfei Tian,Yuanyuan Luo,Fei Peng,Peng Huang,Yongliang Yang,Dapeng Liang,Bing Liu,Qingkai Yang,Huandong Luo,Keith W Kelley,Liu Yin,Qitong Su,Suling Liu,Xinyu Liu,Binhua P Zhou,Wei Cheng,Lingqiang Zhang,Yujia Pan,Jiachuan Yu,Guowang Xu,Dangsheng Li,Sijin Wu,Limei Song ,Ailong Fan ,Jinxin Lü ,Eric W.‐F Lam ,Yan Wang

doi:10.1172/jci121685

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.

Highlights

Patients suffering from cancer often experience a variety of chronic emotional stressors [1], including depression, anxiety, and fear [2, 3]
Even though there was no difference in body weight between the control and stressed groups (Supplemental Figure 1C), tumors from the chronic stress group continued to increase throughout the entire 30-day stress paradigm
Immunohistochemical staining was performed on these tissues, and the results revealed that high serum epinephrine was positively associated with high Lactate dehydrogenase A (LDHA), USP28, MYC, and SLUG protein expression (Figure 6A and Supplemental Figure 7B)

Summary

Introduction

Patients suffering from cancer often experience a variety of chronic emotional stressors [1], including depression, anxiety, and fear [2, 3]. We define what to our knowledge is a novel molecular pathway by which chronic stress acts via β2-adrenergic receptor to elevate LDHA. This leads to a switch to lactate production, and the adjusted pH directs USP28-mediated deubiquitination and stabilization of MYC, thereby promoting stem-like traits in breast cancer.

Results

Discussion

Methods