title: Regulation of Acetate Utilization by Monocarboxylate Transporter 1 (MCT1) in Hepatocellular Carcinoma (HCC).
abstract: Altered energy metabolism is a biochemical fingerprint of cancer cells. Hepatocellular carcinoma (HCC) shows reciprocal [18F]fluorodeoxyglucose (FDG) and [11C]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 [11C]acetate uptake in human HCCs and cell lines. The expression of monocarboxylate transporters (MCTs) was assessed to determine the transporters of [11C]acetate uptake in HCC cell lines and human HCCs with different [11C]acetate uptake. Using two representative cell lines with widely different [11C]acetate uptake (HepG2 for high uptake and Hep3B for low uptake), changes in [11C]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 [11C]acetate uptake showed higher MCT1 expression than other HCC cell lines with low [11C]acetate uptake. MCT1 expression was elevated in human HCCs with high [11C]acetate uptake compared to those with low [11C]acetate uptake. After blocking MCT1 with AR-C155858 or MCT1 knockdown, [11C]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 [11C]acetate uptake. MCT1 may be a new therapeutic target for acetate-dependent HCCs with high [11C]acetate uptake, which can be selected by [11C]acetate PET/CT imaging in clinical practice.
authors.affiliation: Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Jeong Yong
authors.initials: JY
authors.lastname: Jeon
authors.affiliation: Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Misu
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Whang
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
authors.forename: Jung-Whan
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Arthur
authors.initials: A
authors.lastname: Cho
authors.affiliation: Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Mijin
authors.initials: M
authors.lastname: Yun
mesh_terms: D000085:Acetates / Q000378:metabolism*; D002250:Carbon Radioisotopes; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000378:metabolism*; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals; D012189:Retrospective Studies; D027981:Symporters / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000085:Acetates; D002250:Carbon Radioisotopes; D027501:Monocarboxylic Acid Transporters; D019275:Radiopharmaceuticals; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C000615233:Carbon-11