Regulation of Acetate Utilization by Monocarboxylate Transporter 1 (MCT1) in Hepatocellular Carcinoma (HCC)

Altered energy metabolism is a biochemical fingerprint of cancer cells. Hepatocellular carcinoma (HCC) shows reciprocal [(18)F]fluorodeoxyglucose (FDG) and [(11)C]acetate uptake, as revealed by positron emission tomography/computed tomography (PET/CT). Previous studies have focused on the role of FDG uptake in cancer cells. In this study, we evaluated the mechanism and roles of [(11)C]acetate uptake in human HCCs and cell lines. The expression of monocarboxylate transporters (MCTs) was assessed to determine the transporters of [(11)C]acetate uptake in HCC cell lines and human HCCs with different [(11)C]acetate uptake. Using two representative cell lines with widely different [(11)C]acetate uptake (HepG2 for high uptake and Hep3B for low uptake), changes in [(11)C]acetate uptake were measured after treatment with an MCT1 inhibitor or MCT1-targeted siRNA. To verify the roles of MCT1 in cells, oxygen consumption rate and the amount of lipid synthesis were measured. HepG2 cells with high [(11)C]acetate uptake showed higher MCT1 expression than other HCC cell lines with low [(11)C]acetate uptake. MCT1 expression was elevated in human HCCs with high [(11)C]acetate uptake compared to those with low [(11)C]acetate uptake. After blocking MCT1 with AR-C155858 or MCT1 knockdown, [(11)C]acetate uptake in HepG2 cells was significantly reduced. Additionally, inhibition of MCT1 suppressed mitochondrial oxidative phosphorylation, lipid synthesis, and cellular proliferation in HCC cells with high [(11)C]acetate uptake. MCT1 may be a new therapeutic target for acetate-dependent HCCs with high [(11)C]acetate uptake, which can be selected by [(11)C]acetate PET/CT imaging in clinical practice.