SLC1A3 contributes to L-asparaginase resistance in solid tumors.

Autor: Sun J; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands., Nagel R; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Zaal EA; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands., Ugalde AP; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Han R; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands., Proost N; Preclinical Intervention Unit and Pharmacology Unit of the Mouse Clinic for Cancer and Ageing (MCCA), The Netherlands Cancer Institute, Amsterdam, The Netherlands., Song JY; Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Pataskar A; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Burylo A; Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Fu H; Department of Chemical and Pharmaceutical Biology, University of Groningen, Groningen, The Netherlands., Poelarends GJ; Department of Chemical and Pharmaceutical Biology, University of Groningen, Groningen, The Netherlands., van de Ven M; Preclinical Intervention Unit and Pharmacology Unit of the Mouse Clinic for Cancer and Ageing (MCCA), The Netherlands Cancer Institute, Amsterdam, The Netherlands., van Tellingen O; Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Berkers CR; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands., Agami R; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2019 Oct 04; Vol. 38 (21), pp. e102147. Date of Electronic Publication: 2019 Sep 16.
DOI: 10.15252/embj.2019102147
Abstrakt: L-asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.
(© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
Externí odkaz: