A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs.
Amino Acid Transport Systems, Neutral
/ genetics
Antineoplastic Agents
Biochemical Phenomena
Biological Transport
/ genetics
CRISPR-Cas Systems
Cation Transport Proteins
/ genetics
Drug Resistance
/ genetics
Genetic Testing
Humans
Monocarboxylic Acid Transporters
/ genetics
Monosaccharide Transport Proteins
/ genetics
Protein Transport
/ physiology
Solute Carrier Proteins
/ metabolism
Symporters
/ genetics
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
03
07
2019
accepted:
27
01
2020
pubmed:
11
3
2020
medline:
11
4
2020
entrez:
11
3
2020
Statut:
ppublish
Résumé
Solute carriers (SLCs) are the largest family of transmembrane transporters in humans and are major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in a haploid human cell line against 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using an SLC-focused CRISPR-Cas9 library, we identified transporters whose absence induced resistance to the drugs tested. This included dependencies involving the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the screened compounds suggests a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provides an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.
Identifiants
pubmed: 32152546
doi: 10.1038/s41589-020-0483-3
pii: 10.1038/s41589-020-0483-3
pmc: PMC7610918
mid: EMS85610
doi:
Substances chimiques
Amino Acid Transport Systems, Neutral
0
Antineoplastic Agents
0
Cation Transport Proteins
0
Monocarboxylic Acid Transporters
0
Monosaccharide Transport Proteins
0
SLC38A5 protein, human
0
Solute Carrier Proteins
0
Symporters
0
UDP-galactose translocator
0
monocarboxylate transport protein 1
0
solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
469-478Subventions
Organisme : Austrian Science Fund FWF
ID : P 29250
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : W 1232
Pays : Austria
Organisme : European Research Council
ID : 695214
Pays : International
Organisme : European Research Council
ID : 772437
Pays : International
Organisme : Austrian Science Fund FWF
ID : I 2192
Pays : Austria
Commentaires et corrections
Type : CommentIn
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