Exercise‐induced changes in tumour LDH‐B and MCT1 expression are modulated by oestrogen‐related receptor alpha in breast cancer‐bearing BALB/c mice

Abstract

Key pointsr Monocarboxylate transporters (MCTs) and lactate dehydrogenase A (LDH-A) play important roles in sustaining the glycolytic phenotype seen in cancer.r Endurance training improves aerobic capacity; however, whether endurance training alters the metabolic phenotype of a solid tumour, from the perspective of lactate metabolism, is yet to be proven.r This study showed that endurance training decreases expression of the MCT1 basigin (CD147) and LDH-A , and also increases LDH-B expression in solid tumours and attenuates tumour lactate metabolism.r Similar results for MCT1 and LDH-B were found with inhibition of the oestrogen-related receptor alpha (ERRα). The training effects were not additive to the ERRα effects on MCT1 and LDH-B expression in the tumour, which indicated that exercise-induced alterations in MCT1 and LDH-B expression were modulated by ERRα.r These results suggest that endurance training could be a useful tool in cancer therapy, especially in basal-like and luminal-like breast carcinomas.Abstract Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRα) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRα and CD147 in the trained animals. Secondly, the inhibition of ERRα by treatment of MC4-L2 human breast cancer cells with XCT790 (inverse agonist ligand of ERRα) before injection into the animals not only increased LDH-B expression in the tumour, but also decreased MCT1 expression in the CX group in comparison to the C group. The effects of ERRα inhibition were not additive to the training effects on the expressions of MCT1 and LDH-B in the solid tumours. In conclusion, our results suggest that exercise-induced suppression of ERRα expression modulates alterations in solid tumour expression of LDH-B and MCT1 and contributes towards the prevention of tumour development.

Can Exercise-Induced Modulation of the Tumor Physiologic Microenvironment Improve Antitumor Immunity?

“…Aerobic exercise normalizes the immunosuppressive, acidic tumor microenvironment. Treadmill running in mice with mammary carcinomas reduced tumor and circulating lactate concentrations by approximately 17% compared with sedentary counterparts (108). In sarcoma bearing rats (109), treadmill running decreased glucose conversion to lactate by approximately 50% in peripheral macrophages and lymphocytes.…”

Sex Hormones Regulate Rat Hepatic Monocarboxylate Transporter Expression and Membrane Trafficking

“…Hypophysectomized rats, with reduced endogenous testosterone levels, showed increased testicular MCT2 mRNA expression that was reversed with testosterone treatment ex vivo (10). Inhibition of estrogen related receptor alpha decreased MCT1 expression in MC4-L2 human breast cancer -bearing BALB/c mice indicating that estrogen may be involved in MCT1 regulation (11) These data suggest that MCTs are regulated by sex hormones in a tissuespecific manner; however, there is a lack of information in the literature evaluating the role of sex hormones on MCT expression in tissues involved in drug disposition.…”

Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review ofIn VivoPreclinical Data

“…Eight prevention studies (40%) reported significant effects of exercise in modulation of local immune response, tumor metabolism and tumor physiology/angiogenesis. Ten progression studies (38.5%) examined mechanisms underlying the effects of exercise on tumor progression (32, 41, 42, 44, 52, 55, 57, 61, 68, 69). The mechanisms examined included multiple different factors/pathways such as apoptosis, perfusion and immune cell infiltration.…”