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SLC 1A3 contributes to L‐asparaginase resistance in solid tumors
Author(s) -
Sun Jianhui,
Nagel Remco,
Zaal Esther A,
Ugalde Alejandro Piñeiro,
Han Ruiqi,
Proost Natalie,
Song JiYing,
Pataskar Abhijeet,
Burylo Artur,
Fu Haigen,
Poelarends Gerrit J,
Ven Marieke,
Tellingen Olaf,
Berkers Celia R,
Agami Reuven
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102147
Subject(s) - biology , microbiology and biotechnology , cancer research
L‐asparaginase ( ASN ase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASN ase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC 1A3 as a novel contributor to ASN ase resistance in cancer cells. In combination with ASN ase, SLC 1A3 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. SLC 1A3 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 ASN ase stimulates aspartate and glutamate consumptions, and their refilling through SLC 1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC 1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASN ase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC 1A3 in ASN ase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASN ase efficacy with solid tumors.