ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer.
ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer.
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DOI：
10.1111/cas.13448
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发表时间：
2018-01
期刊：
影响因子：
5.7
通讯作者：
Furukawa K
中科院分区：
文献类型：
--
作者：
Esaki N;Ohkawa Y;Hashimoto N;Tsuda Y;Ohmi Y;Bhuiyan RH;Kotani N;Honke K;Enomoto A;Takahashi M;Furukawa K;Furukawa K
神经节苷脂GD2在小细胞肺癌(SCLC)细胞中特异表达，导致细胞增殖和迁移等恶性表型增强。然而，GD2如何促进SCLC细胞的恶性表型还不是很清楚。在这项研究中，为了揭示GD2增加SCLC细胞恶性表型的机制，我们使用了酶介导的自由基源激活结合GD2+SCLC细胞的质谱仪。因此，我们确定了ASC氨基酸转运蛋白2(ASCT2)，它是一种主要的谷氨酰胺转运蛋白，与GD2协调工作。结果表明，在GD2+SCLC细胞中，ASCT2在糖脂丰富的微域/筏中高度表达，在邻近连接实验和免疫细胞染色中均与GD2共定位，在免疫沉淀/TLC免疫染色中与GD2结合。GD2+小细胞肺癌细胞的恶性表型可被谷氨酰胺摄取增强，并被ASCT2的特异性抑制剂L-γ-谷氨酰-对硝基苯胺通过减少p70S6K1和S6的磷酸化而抑制。这些结果表明，ASCT2增强了GD2+SCLC细胞糖脂富含微域/筏的谷氨酰胺摄取，通过增加mTOR复合体1信号轴的磷酸化而促进细胞的增殖和迁移。
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.
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DOI：
10.1073/pnas.0710346105
发表时间：
2008-05-27
影响因子：
11.1
作者：
Kotani, Norihiro;Gu, Jianguo;Honke, Koichi
通讯作者：
Honke, Koichi
影响因子：
45.3
作者：
Kushner, Brian H.;Kramer, Kim;Cheung, Nai-Kong V.
通讯作者：
Cheung, Nai-Kong V.
影响因子：
64.8
作者：
Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide
通讯作者：
Ruggero, Davide
DOI：
10.1083/jcb.201102090
发表时间：
2011-09-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Liu L;Parent CA
通讯作者：
Parent CA
影响因子：
6.4
作者：
Cheung NK;Cheung IY;Kramer K;Modak S;Kuk D;Pandit-Taskar N;Chamberlain E;Ostrovnaya I;Kushner BH
通讯作者：
Kushner BH