The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5)
| Autor: | Sandy Giuliano, Jérôme Durivault, Jacques Pouysségur, Michael F. Wempe, Milica Vučetić, Yann Cormerais, Eric Tambutté, Hitoshi Endou, Pierre André Massard, Scott K. Parks, Valérie Vial |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Amino Acid Transport System ASC
0301 basic medicine Lung Neoplasms Glutamine Mice Nude Antineoplastic Agents P70-S6 Kinase 1 mTORC1 Adenocarcinoma Mechanistic Target of Rapamycin Complex 1 Biochemistry Large Neutral Amino Acid-Transporter 1 Minor Histocompatibility Antigens Gene Knockout Techniques 03 medical and health sciences cell metabolism Cell Line Tumor Membrane Transport Modulators cancer Animals Humans Amino acid transporter Molecular Biology Cell Proliferation chemistry.chemical_classification amino acid transport Cell growth Chemistry mammalian target of rapamycin (mTOR) Cell Biology ASCT2 LAT1 Recombinant Proteins Absorption Physiological Clone Cells Neoplasm Proteins Cell biology Solute carrier family Amino acid 030104 developmental biology Cell culture Colonic Neoplasms Female CRISPR-Cas Systems amino acid Gene Deletion Neoplasm Transplantation |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra117.001342 |
| Popis: | The transporters for glutamine and essential amino acids, ASCT2 (solute carrier family 1 member 5, SLC1A5) and LAT1 (solute carrier family 7 member 5, SLC7A5), respectively, are overexpressed in aggressive cancers and have been identified as cancer-promoting targets. Moreover, previous work has suggested that glutamine influx via ASCT2 triggers essential amino acids entry via the LAT1 exchanger, thus activating mechanistic target of rapamycin complex 1 (mTORC1) and stimulating growth. Here, to further investigate whether these two transporters are functionally coupled, we compared the respective knockout (KO) of either LAT1 or ASCT2 in colon (LS174T) and lung (A549) adenocarcinoma cell lines. Although ASCT2KO significantly reduced glutamine import (>60% reduction), no impact on leucine uptake was observed in both cell lines. Although an in vitro growth-reduction phenotype was observed in A549-ASCT2KO cells only, we found that genetic disruption of ASCT2 strongly decreased tumor growth in both cell lines. However, in sharp contrast to LAT1KO cells, ASCT2KO cells displayed no amino acid (AA) stress response (GCN2/EIF2a/ATF4) or altered mTORC1 activity (S6K1/S6). We therefore conclude that ASCT2KO reduces tumor growth by limiting AA import, but that this effect is independent of LAT1 activity. These data were further supported by in vitro cell proliferation experiments performed in the absence of glutamine. Together these results confirm and extend ASCT2's pro-tumoral role and indicate that the proposed functional coupling model of ASCT2 and LAT1 is not universal across different cancer types. |
| Databáze: | OpenAIRE |
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