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

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