Lactate receptor HCAR1 regulates cell growth, metastasis and maintenance of cancer-specific energy metabolism in breast cancer cells

Under aerobic conditions, the preferential use of anaerobic glycolysis by tumour cells leads to a high level of lactate accumulation in tumour microenvironment. Lactate acts not only as a cellular energy source but also as a signalling molecule that regulates cancer cell growth, metastasis and metabolism. It has been reported that a G-protein-coupled receptor for lactate named hydroxycarboxylic acid receptor 1 (HCAR1) is highly expressed in numerous types of cancer, but the detailed mechanism remains unclear. In the present study, it was reported that HCAR1 is highly expressed in breast cancer cells. Genetic deletion of HCAR1 in MCF7 cells leads to reduced cell proliferation and migration. Moreover, it was observed that knockout (KO) of HCAR1 attenuated the expression and activity of phosphofructokinase and hexokinase, key rate-limiting enzymes in glycolysis. Using an extracellular flux analyzer, it was showed that KO of HCAR1 promoted a metabolic shift towards a decreased glycolysis state, as evidenced by a decreased extracellular acidification rate and increased oxygen consumption rate in MCF7 cells. Taken together, our results suggested that lactate acts through HCAR1 as a metabolic regulator in breast cancer cells that may be therapeutically exploited.