ASCT2 defined by enzyme-mediated activation of radical sources enhances malignancy of GD2-plus 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 mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we performed enzyme-mediated activation of radical sources combined with mass spectrometry in GD2 positive (+) 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 co-localized with GD2 in proximity ligation assay and immunocytostaining, and bound with GD2 in immuneoprecipitation/TLC-immunostaining. Malignant phenotypes of GD2(+) SCLC cells were enhanced via glutamine uptake, and were suppressed by L-γ-glutamyl-p-nitroanilide, a specific inhibitor of ASCT2, via reduced phosphorylation of p70 S6K1 and S6. These results suggested that ASCT2 enhances glutamine uptake in GEM/rafts in GD2(+) SCLC cells, leading to the enhancement of cell proliferation and migration through increased phosphorylation of mTORC1 signaling axis.

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