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

Abstract

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: Mijin Yun, Seong-Hye Bang, Jae Woo Kim, Jun Young Park, Kyoung Sup Kim, Jong Doo Lee
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 50 Issue 8 Pg. 1222-8 (Aug 2009) ISSN: 0161-5505 [Print] United States
• PMID: 19617323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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