UNLABELLED: We analyzed the pattern of (11)C-acetate and (18)F-FDG uptake on PET/CT in patients with hepatocellular carcinoma (HCC). We also assessed the expression of important regulatory enzymes related to glycolysis and lipid synthesis in relation to (18)F-FDG and (11)C-acetate uptake in human HCC cell lines. The significance of (11)C-acetate uptake regulation was further evaluated with regard to cell viability. METHODS: (18)F-FDG and (11)C-acetate uptake patterns in HCC in 11 patients and in 5 HCC cell lines were assessed. We evaluated the gene expression of metabolic enzymes related to glycolysis and lipid synthesis in a cell line with the highest (18)F-FDG uptake and another cell line with the highest (11)C-acetate uptake. They included hexokinase II, adenosine triphosphate citrate lyase, acetyl coenzyme A (CoA) synthetase 1 (ACSS1), acetyl CoA synthetase 2 (ACSS2), acetyl CoA carboxylase, and fatty acid synthase. In a cell line with high (11)C-acetate uptake, the enzymatic activities of ACSS1 and ACSS2 were blocked using respective small, interfering RNAs (siRNAs), and the impact on (11)C-acetate uptake and cell viability was assessed. RESULTS: In all 11 patients and 4 of the 5 cell lines, the uptake patterns of the 2 radiotracers were complementary. ACSS1 and ACSS2 were highly expressed in a cell line with low (18)F-FDG uptake and high (11)C-acetate uptake, whereas only ACSS2 was expressed in a cell line with high (18)F-FDG uptake and low (11)C-acetate uptake. Fatty acid synthase expression was seen in cells with high (18)F-FDG or (11)C-acetate uptake. These findings indicate the possibility that both glucose and acetate can be a compensatory carbon source for lipid synthesis in cancer. Transient transfection with ACSS1 or ACSS2 siRNA in cells with high (11)C-acetate uptake decreased (11)C-acetate uptake and cell viability. CONCLUSION: The patterns of (18)F-FDG and (11)C-acetate uptake seemed to complement each other in both human HCC and HCC cell lines. Fatty acid synthase expression was seen in cells with high (18)F-FDG or (11)C-acetate uptake, suggesting glucose- or acetate-dependent lipid synthesis. Acetyl CoA synthetase appears to be important in (11)C-acetate uptake and acetate-dependent lipid synthesis for the growth of cancer cells with a low-glycolysis phenotype. Inhibition of acetyl CoA synthetase in these cells may be promising for anticancer treatment.
UNLABELLED: We analyzed the pattern of (11)C-acetate and (18)F-FDG uptake on PET/CT in patients with hepatocellular carcinoma (HCC). We also assessed the expression of important regulatory enzymes related to glycolysis and lipid synthesis in relation to (18)F-FDG and (11)C-acetate uptake in human HCC cell lines. The significance of (11)C-acetate uptake regulation was further evaluated with regard to cell viability. METHODS: (18)F-FDG and (11)C-acetate uptake patterns in HCC in 11 patients and in 5 HCC cell lines were assessed. We evaluated the gene expression of metabolic enzymes related to glycolysis and lipid synthesis in a cell line with the highest (18)F-FDG uptake and another cell line with the highest (11)C-acetate uptake. They included hexokinase II, adenosine triphosphate citrate lyase, acetyl coenzyme A (CoA) synthetase 1 (ACSS1), acetyl CoA synthetase 2 (ACSS2), acetyl CoA carboxylase, and fatty acid synthase. In a cell line with high (11)C-acetate uptake, the enzymatic activities of ACSS1 and ACSS2 were blocked using respective small, interfering RNAs (siRNAs), and the impact on (11)C-acetate uptake and cell viability was assessed. RESULTS: In all 11 patients and 4 of the 5 cell lines, the uptake patterns of the 2 radiotracers were complementary. ACSS1 and ACSS2 were highly expressed in a cell line with low (18)F-FDG uptake and high (11)C-acetate uptake, whereas only ACSS2 was expressed in a cell line with high (18)F-FDG uptake and low (11)C-acetate uptake. Fatty acid synthase expression was seen in cells with high (18)F-FDG or (11)C-acetate uptake. These findings indicate the possibility that both glucose and acetate can be a compensatory carbon source for lipid synthesis in cancer. Transient transfection with ACSS1 or ACSS2 siRNA in cells with high (11)C-acetate uptake decreased (11)C-acetate uptake and cell viability. CONCLUSION: The patterns of (18)F-FDG and (11)C-acetate uptake seemed to complement each other in both human HCC and HCC cell lines. Fatty acid synthase expression was seen in cells with high (18)F-FDG or (11)C-acetate uptake, suggesting glucose- or acetate-dependent lipid synthesis. Acetyl CoA synthetase appears to be important in (11)C-acetate uptake and acetate-dependent lipid synthesis for the growth of cancer cells with a low-glycolysis phenotype. Inhibition of acetyl CoA synthetase in these cells may be promising for anticancer treatment.
Authors: Alexander J Lakhter; James Hamilton; Raymond L Konger; Nickolay Brustovetsky; Hal E Broxmeyer; Samisubbu R Naidu Journal: J Biol Chem Date: 2016-08-18 Impact factor: 5.157
Authors: Sarah A Comerford; Zhiguang Huang; Xinlin Du; Yun Wang; Ling Cai; Agnes K Witkiewicz; Holly Walters; Mohammed N Tantawy; Allie Fu; H Charles Manning; Jay D Horton; Robert E Hammer; Steven L McKnight; Benjamin P Tu Journal: Cell Date: 2014-12-18 Impact factor: 41.582
Authors: Steven Zhao; AnnMarie Torres; Ryan A Henry; Sophie Trefely; Martina Wallace; Joyce V Lee; Alessandro Carrer; Arjun Sengupta; Sydney L Campbell; Yin-Ming Kuo; Alexander J Frey; Noah Meurs; John M Viola; Ian A Blair; Aalim M Weljie; Christian M Metallo; Nathaniel W Snyder; Andrew J Andrews; Kathryn E Wellen Journal: Cell Rep Date: 2016-10-18 Impact factor: 9.423