Differences in accumulation and the transport mechanism of l- and d-methionine in high- and low-grade human glioma cells

Masato Kobayashi; Asuka Mizutani; Kodai Nishi; Syuichi Nakajima; Naoto Shikano; Ryuichi Nishii; Kazuki Fukuchi; Keiichi Kawai

doi:10.1016/j.nucmedbio.2016.09.003

Differences in accumulation and the transport mechanism of l- and d-methionine in high- and low-grade human glioma cells

Nucl Med Biol. 2017 Jan:44:78-82. doi: 10.1016/j.nucmedbio.2016.09.003. Epub 2016 Sep 14.

Authors

Masato Kobayashi¹, Asuka Mizutani², Kodai Nishi³, Syuichi Nakajima⁴, Naoto Shikano⁴, Ryuichi Nishii⁵, Kazuki Fukuchi⁶, Keiichi Kawai⁷

Affiliations

¹ Wellness Promotion Science Center, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan. Electronic address: kobayasi@mhs.mp.kanazawa-u.ac.jp.
² Graduate School of Medicine, Division of Health Sciences, Osaka University, Japan; Department of Radiology, Kanazawa University Hospital, Japan.
³ Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
⁴ Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Japan.
⁵ Molecular Imaging Center, National Institute of Radiological Sciences, Japan.
⁶ Graduate School of Medicine, Division of Health Sciences, Osaka University, Japan.
⁷ School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan; Biomedical Imaging Research Center, University of Fukui, Fukui, Japan.

PMID: 27835793
DOI: 10.1016/j.nucmedbio.2016.09.003

Abstract

Introduction: Although [S-methyl-11C]-labeled L-methionine and D-methionine (¹¹C-L-MET and ¹¹C-D-MET) are useful radiotracers for positron emission tomography imaging of brain tumors, it is not known whether the accumulation and transport mechanisms underlying uptake of ¹¹C-D-MET and ¹¹C-L-MET are the same. ¹¹C-L-MET is mainly taken up by the amino acid transport system L. We evaluated accumulation and the transport mechanism of D-MET in high- and low-grade human glioma cells in vitro.

Methods: The expression of transport system genes in high- (A172 and T98G) and low-grade (SW1088 and Hs683) glioma cells was quantitatively analyzed. Accumulation of [S-methyl-³H]-L-MET (³H-L-MET) and [S-methyl-³H]-D-MET (³H-D-MET) in these cells was compared during 60min of incubation. The transport mechanism of ³H-L-MET and ³H-D-MET was investigated by incubating the cells with these compounds and examining the effect of the inhibitors 2-amino-2-norbornane-carboxylic acid or α-(methylamino) isobutyric acid.

Results: Absolute expression levels of system L and system alanine-serine-cysteine (ASC) in high-grade glioma cells were higher than in low-grade cells. In high-grade glioma cells, expression of system ASC genes was higher than that of system L genes. ³H-D-MET, which is transported by systems L and ASC, accumulated at higher levels than ³H-L-MET at all incubation times because ³H-D-MET is more sensitive to system ASC than ³H-L-MET. Conversely, in low-grade glioma cells with lower expression of system L and ASC, ³H-D-MET accumulated at higher levels than ³H-L-MET in early incubation times because ³H-D-MET may be more sensitive to system ASC than system L.

Conclusion: ³H-D-MET was mainly transported by systems L and ASC and sensitive to system ASC, whereas ³H-L-MET was transported by system L in human glioma cells. In vitro, the accumulation of ³H-D-MET was significantly higher than that of ³H-L-MET during the entire incubation time in high-grade glioma cells, and in early incubation times in low-grade glioma cells.

Keywords: Amino acid transport system; Glioma; Methionine; Positron emission tomography.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport Systems / metabolism
Biological Transport
Carbon Radioisotopes
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Glioma / metabolism
Glioma / pathology*
Humans
Methionine / chemistry*
Methionine / metabolism*
Neoplasm Grading
Positron-Emission Tomography
Stereoisomerism

Substances

Amino Acid Transport Systems
Carbon Radioisotopes
Methionine