Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase: implications for the mechanism of acetate PET

Yoshii, Yukie; Waki, Atsuo; Furukawa, Takako; Kiyono, Yasushi; Mori, Tetsuya; Yoshii, Hiroshi; Kudo, Takashi; Okazawa, Hidehiko; Welch, Michael J.; Fujibayashi, Yasuhisa

doi:10.1016/j.nucmedbio.2009.05.006

« Previous Next »Nuclear Medicine and Biology
Volume 36, Issue 7 , Pages 771-777, October 2009

Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase: implications for the mechanism of acetate PET

Yukie Yoshii
- Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan
Atsuo Waki
- Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan
Takako Furukawa
- Molecular Imaging Center, National Institute of Radiological Sciences, Anagawa, Chiba 263-8555, Japan
Yasushi Kiyono
- Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan
Tetsuya Mori
- Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Hiroshi Yoshii
- Faculty of Medical Sciences, Department of Biochemistry and Bioinformative Science, University of Fukui, Eiheiji, Fukui 910-1193, Japan
Takashi Kudo
- Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan
Hidehiko Okazawa
- Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan
Michael J. Welch
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Yasuhisa Fujibayashi
- Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan
- Molecular Imaging Center, National Institute of Radiological Sciences, Anagawa, Chiba 263-8555, Japan
- Corresponding author. Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan. Tel.: +81 776 61 8491; fax: +81 776 61 8170.

Received 8 April 2009; received in revised form 19 May 2009; accepted 28 May 2009. published online 30 July 2009.

Abstract

Introduction

[1-¹¹C]Acetate positron emission tomography (PET) is used for myocardial studies. In the myocardium, mitochondrial acetyl-CoA synthetase (ACSS1) mainly contributes to the radiopharmaceutical uptake. [1-¹¹C]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

[1-¹⁴C]Acetate uptake and ACSS2 expression were examined in four tumor cell lines under normoxia or hypoxia. An ACSS2 knockdown study was also performed.

Results

[1-¹⁴C]Acetate uptake was increased in the tumor cells under hypoxia. This pattern followed that of ACSS2 expression. The incorporated ¹⁴C was mostly distributed in the lipid-soluble fractions, and this tendency increased under hypoxia. ACSS2 knockdown led to a corresponding reduction in [1-¹⁴C]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.

Keywords: Acetate, Acetyl-CoA synthetase, PET, Hypoxia, Tumor