Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells
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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.author | Broer, Angelika | |
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dc.contributor.author | Gauthier-Coles, Gregory | |
dc.contributor.author | Rahimi, Farid | |
dc.contributor.author | van Geldermalsen, Michelle | |
dc.contributor.author | Dorsch, Dieter | |
dc.contributor.author | Wegener, Ansgar | |
dc.contributor.author | Holst, Jeff | |
dc.contributor.author | Broer, Stefan | |
dc.date.accessioned | 2021-04-16T02:56:54Z | |
dc.identifier.issn | 0021-9258 | |
dc.identifier.uri | http://hdl.handle.net/1885/230033 | |
dc.description.abstract | 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 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.sponsorship | This 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.mimetype | application/pdf | |
dc.language.iso | en_AU | |
dc.publisher | American Society for Biochemistry and Molecular Biology Inc | |
dc.rights | © 2019 Bröer et al. | |
dc.source | Journal of Biological Chemistry | |
dc.title | Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 294 | |
dcterms.dateAccepted | 2019-01-08 | |
dc.date.issued | 2019-01-11 | |
local.identifier.absfor | 060104 - Cell Metabolism | |
local.identifier.absfor | 060110 - Receptors and Membrane Biology | |
local.identifier.ariespublication | u4008405xPUB160 | |
local.type.status | Published Version | |
local.contributor.affiliation | Broer, Angelika, College of Science, ANU | |
local.contributor.affiliation | Gauthier-Coles, Gregory, College of Science, ANU | |
local.contributor.affiliation | Rahimi, Ahmed (Farid), College of Science, ANU | |
local.contributor.affiliation | van Geldermalsen, Michelle, University of Sydney | |
local.contributor.affiliation | Dorsch, Dieter, Merck KGaA | |
local.contributor.affiliation | Wegener, Ansgar, Merck KGaA | |
local.contributor.affiliation | Holst, Jeff, University of New South Wales | |
local.contributor.affiliation | Broer, Stefan, College of Science, ANU | |
local.description.embargo | 2099-12-31 | |
dc.relation | http://purl.org/au-research/grants/arc/DP180101702 | |
local.bibliographicCitation.startpage | 4012 | |
local.bibliographicCitation.lastpage | 4026 | |
local.identifier.doi | 10.1074/jbc.RA118.006378 | |
local.identifier.absseo | 920111 - Nervous System and Disorders | |
dc.date.updated | 2020-11-23T11:31:24Z | |
local.identifier.scopusID | 2-s2.0-85062962626 | |
Collections | ANU Research Publications |
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