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Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells

Broer, Angelika; Gauthier-Coles, Gregory; Rahimi, Farid; van Geldermalsen, Michelle; Dorsch, Dieter; Wegener, Ansgar; Holst, Jeff; Broer, Stefan

Description

The neutral amino acid transporter solute carrier family 1 member 5 (SLC1A5 or ASCT2) is overexpressed in many cancers. To identify its roles in tumors, we employed 143B osteosarcoma cells and HCC1806 triple-negative breast cancer cells with or without ASCT2 deletion. ASCT2ko 143B cells grew well in standard culture media, but ASCT2 was required for optimal growth at < 0.5 mM glutamine, with tumor spheroid growth and monolayer migration of 143B ASCT2ko cells being strongly impaired at lower...[Show more]

dc.contributor.authorBroer, Angelika
dc.contributor.authorGauthier-Coles, Gregory
dc.contributor.authorRahimi, Farid
dc.contributor.authorvan Geldermalsen, Michelle
dc.contributor.authorDorsch, Dieter
dc.contributor.authorWegener, Ansgar
dc.contributor.authorHolst, Jeff
dc.contributor.authorBroer, Stefan
dc.date.accessioned2021-04-16T02:56:54Z
dc.identifier.issn0021-9258
dc.identifier.urihttp://hdl.handle.net/1885/230033
dc.description.abstractThe neutral amino acid transporter solute carrier family 1 member 5 (SLC1A5 or ASCT2) is overexpressed in many cancers. To identify its roles in tumors, we employed 143B osteosarcoma cells and HCC1806 triple-negative breast cancer cells with or without ASCT2 deletion. ASCT2ko 143B cells grew well in standard culture media, but ASCT2 was required for optimal growth at < 0.5 mM glutamine, with tumor spheroid growth and monolayer migration of 143B ASCT2ko cells being strongly impaired at lower glutamine concentrations. However, the ASCT2 deletion did not affect matrix-dependent invasion. ASCT2ko 143B xenografts in nude mice exhibited a slower onset of growth and a higher number of small tumors than ASCT2wt 143B xenografts, but did not differ in average tumor size 25 days after xenotransplantation. ASCT2 deficiency was compensated by increased levels of sodium neutral amino acid transporter 1 (SNAT1 or SLC38A1) and SNAT2 (SLC38A2) in ASCT2ko 143B cells, mediated by a GCN2 EIF2alpha kinase (GCN2)-dependent pathway, but this compensation was not observed in ASCT2ko HCC1806 cells. Combined SNAT1 silencing and GCN2 inhibition significantly inhibited growth of ASCT2ko HCC1806 cells, but not of ASCT2ko 143B cells. Similarly, pharmacological inhibition of L-type amino acid transporter 1 (LAT1) and GCN2 significantly inhibited growth of ASCT2ko HCC1806 cells, but not of ASCT2ko 143B cells. We conclude that cancer cells with reduced transporter plasticity are more vulnerable to disruption of amino acid homeostasis than cells with a full capacity to upregulate redundant transporters by an integrated stress response.
dc.description.sponsorshipThis work was supported in part by a Merck KGaA speed grant (to S. B.), Australian Research Council Discovery Project Grant DP180101702 (to S. B.), and Cancer Council New South Wales Grants RG17-04 and RG18-06 (to J. H.).
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc
dc.rights© 2019 Bröer et al.
dc.sourceJournal of Biological Chemistry
dc.titleAblation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume294
dcterms.dateAccepted2019-01-08
dc.date.issued2019-01-11
local.identifier.absfor060104 - Cell Metabolism
local.identifier.absfor060110 - Receptors and Membrane Biology
local.identifier.ariespublicationu4008405xPUB160
local.type.statusPublished Version
local.contributor.affiliationBroer, Angelika, College of Science, ANU
local.contributor.affiliationGauthier-Coles, Gregory, College of Science, ANU
local.contributor.affiliationRahimi, Ahmed (Farid), College of Science, ANU
local.contributor.affiliationvan Geldermalsen, Michelle, University of Sydney
local.contributor.affiliationDorsch, Dieter, Merck KGaA
local.contributor.affiliationWegener, Ansgar, Merck KGaA
local.contributor.affiliationHolst, Jeff, University of New South Wales
local.contributor.affiliationBroer, Stefan, College of Science, ANU
local.description.embargo2099-12-31
dc.relationhttp://purl.org/au-research/grants/arc/DP180101702
local.bibliographicCitation.startpage4012
local.bibliographicCitation.lastpage4026
local.identifier.doi10.1074/jbc.RA118.006378
local.identifier.absseo920111 - Nervous System and Disorders
dc.date.updated2020-11-23T11:31:24Z
local.identifier.scopusID2-s2.0-85062962626
CollectionsANU Research Publications

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