The importance of acetyl coenzyme A synthetase for 11C-acetate uptake and cell survival in hepatocellular carcinoma

J Nucl Med. 2009 Aug;50(8):1222-8. doi: 10.2967/jnumed.109.062703. Epub 2009 Jul 17.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetate-CoA Ligase / metabolism*
  • Acetates / pharmacokinetics*
  • Adult
  • Aged
  • Carbon / pharmacokinetics*
  • Carcinoma, Hepatocellular / diagnostic imaging
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Cell Survival
  • Fatty Acid Synthases / metabolism*
  • Female
  • Fluorodeoxyglucose F18 / pharmacokinetics*
  • Humans
  • Liver Neoplasms / diagnostic imaging
  • Liver Neoplasms / metabolism*
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Radionuclide Imaging
  • Radiopharmaceuticals / pharmacokinetics*

Substances

  • Acetates
  • Radiopharmaceuticals
  • carbon-11 acetate
  • Fluorodeoxyglucose F18
  • Carbon
  • Fatty Acid Synthases
  • Acetate-CoA Ligase