ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer.

Abstract

Ganglioside GD2 is specifically expressed in small-cell lung cancer (SCLC) cells, leading to enhancement of malignant phenotypes, such as cell proliferation and migration. However, how GD2 promotes malignant phenotypes in SCLC cells is not well known. In this study, to reveal the mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we used enzyme-mediated activation of radical sources combined with mass spectrometry in GD2+ SCLC cells. Consequently, we identified ASC amino acid transporter 2 (ASCT2), a major glutamine transporter, which coordinately works with GD2. We showed that ASCT2 was highly expressed in glycolipid-enriched microdomain/rafts in GD2+ SCLC cells, and colocalized with GD2 in both proximity ligation assay and immunocytostaining, and bound with GD2 in immunoprecipitation/TLC immunostaining. Malignant phenotypes of GD2+ SCLC cells were enhanced by glutamine uptake, and were suppressed by L-γ-glutamyl-p-nitroanilide, a specific inhibitor of ASCT2, through reduced phosphorylation of p70 S6K1 and S6. These results suggested that ASCT2 enhances glutamine uptake in glycolipid-enriched microdomain/rafts in GD2+ SCLC cells, leading to the enhancement of cell proliferation and migration through increased phosphorylation of the mTOR complex 1 signaling axis.

• Authors: Nobutoshi Esaki, Yuki Ohkawa, Noboru Hashimoto, Yuhsuke Tsuda, Yuhsuke Ohmi, Robiul H Bhuiyan, Norihiro Kotani, Koichi Honke, Atsushi Enomoto, Masahide Takahashi, Keiko Furukawa, Koichi Furukawa
• Journal: Cancer science (Cancer Sci) Vol. 109 Issue 1 Pg. 141-153 (Jan 2018) ISSN: 1349-7006 [Electronic] England
• PMID: 29151270 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Amino Acid Transport System ASC
• Gangliosides
• Minor Histocompatibility Antigens
• SLC1A5 protein, human
• Glutamine
• ganglioside, GD2
• gamma-glutamine-4-nitroanilide

Topics

• Amino Acid Transport System ASC (metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Gangliosides (metabolism)
• Glutamine (analogs & derivatives, metabolism, pharmacology)
• Humans
• Lung Neoplasms (metabolism)
• Membrane Microdomains (metabolism)
• Minor Histocompatibility Antigens (metabolism)
• Small Cell Lung Carcinoma (metabolism)