title: Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase: implications for the mechanism of acetate PET.
abstract: BACKGROUND
  [1-(11)C]Acetate positron emission tomography (PET) is used for myocardial studies. In the myocardium, mitochondrial acetyl-CoA synthetase (ACSS1) mainly contributes to the radiopharmaceutical uptake. [1-(11)C]Acetate PET is also used for tumor diagnosis; however, the uptake mechanism of radiolabeled acetate in tumors remains unclear. Our previous study reported that cytosolic acetyl-CoA synthetase (ACSS2) was expressed in tumor cells and up-regulated under hypoxia, whereas expression of ACSS1 was negligible regardless of the oxygen conditions. We also indicated that ACSS2 is a bidirectional enzyme that controls acetyl-CoA/acetate metabolism in tumor cells. In this study, to elucidate the basic mechanism of tumor acetate uptake, we focused on ACSS2 and investigated the role of ACSS2 in the uptake of radiolabeled acetate in tumor cells.
  
  
  METHODS
  [1-(14)C]Acetate uptake and ACSS2 expression were examined in four tumor cell lines under normoxia or hypoxia. An ACSS2 knockdown study was also performed.
  
  
  RESULTS
  [1-(14)C]Acetate uptake was increased in the tumor cells under hypoxia. This pattern followed that of ACSS2 expression. The incorporated (14)C was mostly distributed in the lipid-soluble fractions, and this tendency increased under hypoxia. ACSS2 knockdown led to a corresponding reduction in [1-(14)C]acetate uptake in all tumor cell lines examined under normoxia and hypoxia.
  
  
  CONCLUSIONS
  ACSS2 plays an important role in the uptake of radiolabeled acetate in tumor cells, which is different from that in the myocardium, which mainly involves ACSS1. The uptake of radiolabeled acetate in tumors increased under hypoxia along with up-regulation of ACSS2 expression. This suggests a possible mechanism for acetate PET for tumors.
authors.affiliation: Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yoshii
authors.forename: Atsuo
authors.initials: A
authors.lastname: Waki
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshii
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Okazawa
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
mesh_terms: D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism*; D000085:Acetates / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002250:Carbon Radioisotopes / Q000737:chemistry; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003600:Cytosol / Q000201:enzymology*; D015972:Gene Expression Regulation, Neoplastic; D007553:Isotope Labeling; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography; D011851:Radioactivity; D013997:Time Factors
chemical_list: D000085:Acetates; D002250:Carbon Radioisotopes; D000106:Acetate-CoA Ligase