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


CONCLUSIONS
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.
Yun
Mijin
M
Division of Nuclear Medicine, Department of Radiology, Yonsei University College of Medicine, Seodaemoon-ku, Seoul, Republic of Korea.
Bang
Seong-Hye
SH
Kim
Jae Woo
JW
Park
Jun Young
JY
Kim
Kyoung Sup
KS
Lee
Jong Doo
JD
D000106:Acetate-CoA Ligase / Q000378:metabolism*; D000085:Acetates / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D002244:Carbon / Q000493:pharmacokinetics*; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D064429:Fatty Acid Synthases / Q000378:metabolism*; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*
D000085:Acetates; D019275:Radiopharmaceuticals; C438206:carbon-11 acetate; D019788:Fluorodeoxyglucose F18; D002244:Carbon; D064429:Fatty Acid Synthases; D000106:Acetate-CoA Ligase