Disruption of Amino Acid Homeostasis by Novel ASCT2 Inhibitors Involves Multiple Targets
Open accessAbstract
The glutamine transporter ASCT2 (SLC1A5) is actively investigated as an oncological target, but the field lacks efficient ASCT2 inhibitors. A new group of ASCT2 inhibitors, 2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids (AABA) were developed recently and shown to suppress tumor growth in preclinical in vivo models. To test its specificity, we deleted ASCT2 in two human cancer cell lines. Surprisingly, growth of parental and ASCT2-knockout cells was equally sensitive to AABA compounds. AABA compounds inhibited glutamine transport in cells lacking ASCT2, but not in parental cells. Deletion of ASCT2 and amino acid depletion induced expression of SNAT2 (SLC38A2), the activity of which was inhibited by AABA compounds. They also potently inhibited isoleucine uptake via LAT1 (SLC7A5), a transporter that is upregulated in cancer cells together with ASCT2. Inhibition of SNAT2 and LAT1 was confirmed by recombinant expression in Xenopus laevis oocytes. The reported reduction of tumor growth in pre-clinical models may be explained by a significant disruption of amino acid homeostasis.
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GPNA also inhibits other glutamine transporters such as SLC38A1, and V-9302 is effective even in SLC1A5 knockout models.
“However, other researchers have argued that controversial issues exist because GPNA also inhibits other glutamine transporters, such as SLC38A1, and V-9302 is effective even in SLC1A5 knockout models206,207.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [206]
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References 37 · Cited by 124
- Authors
- Bröer, A., Fairweather, S., & Bröer, S.
- Affiliations
- Australian National University (AU)
- Corresponding author
- Bröer, Stefan
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2018-07-19
- Volume
- 9
- Pages
- 785-785
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC6060247
- OpenAlex
- W2884192701
- Cited by
- 124
- References
- 37
- Citations by year
- 2026: 6 · 2025: 20 · 2024: 13 · 2023: 13 · 2022: 22 · 2021: 18 · 2020: 16 · 2019: 14 · 2018: 2
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- ANU Open Research (Australian National University) (submittedVersion, cc-by)
- Funders
- Australian Research Council (DP180101702)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- ASCT2, SLC1A5, glutamine transporter, amino acid homeostasis, SNAT2, LAT1, glutamine transport, tumor growth inhibition, cancer cell lines, transporter specificity
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