Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC
Open accessAbstract
Glutaminase 1 (GLS1) expression is increased in non-small cell lung cancer (NSCLC). GLS1 knockdown using siRNA or inhibition using bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) induced cell cycle arrest with significant reduction of ATP level while levels of reactive oxygen species or glutathione were not affected in NSCLC cell lines. Recently we found that NSCLC significantly depends on cytosol NADH for ATP production. GLS1 remarkably contributes to ATP production through transferring cytosolic NADH into mitochondria via malate-aspartate shuttle by supply of glutamate in NSCLC. Regulation of malate-aspartate shuttle by knockdown or inhibition of glutamic-oxaloacetic transaminase 2 or malate dehydrogenase 2 mimicked GLS1 knockdown, which induced cell death with ATP reduction in NSCLC. Therefore, GLS1 inhibition induced cell cycle arrest with ATP depletion by glutamate reduction. Dual inhibition with BPTES and thymidylate synthase inhibitor, 5-fluorouracil (5-FU), elicits cell death synergistically through cell cycle arrest in NSCLC. A preclinical xenograft model of NSCLC showed remarkable anti-tumour effect synergistically in the BPTES and 5-FU dual therapy group.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
GLS1 knockdown significantly suppresses NADH and ATP production in cancer cells, so glutamate and α-KG supply for MAS activity is critical for ATP production in cancer cells.
“Glutamate and α-KG serve as important exchangers in the MAS, and since GLS1 knockdown significantly suppresses NADH and ATP production in cancer cells143, the supply of glutamate and α-KG for the induction of MAS activity is evidently critical for ATP production in cancer cells”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [143]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 19 · Cited by 56
- Authors
- Lee, J.-S., Kang, J. H., Lee, S.-H., Hong, D., Son, J., Hong, K. M., Song, J., & Kim, S.-Y.
- Affiliations
- Yonsei University (KR)
- National Cancer Center (KR)
- University of Ulsan (KR)
- Corresponding author
- Kim, Soo-Youl
- Venue
- Cell Death & Disease
- Published
- 2016-12-08
- Volume
- 7
- Issue
- 12
- Pages
- e2511-e2511
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5261012
- OpenAlex
- W2560767781
- Cited by
- 56
- References
- 19
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 13 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 1 · 2017: 3
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- GLS1, thymidylate synthase, non-small cell lung cancer, BPTES, 5-fluorouracil, synergistic cell death, ATP depletion, malate-aspartate shuttle, glutamate, MDH2, cell cycle arrest, xenograft models
- MeSH terms
- A549 Cells, Adenosine Triphosphate, Animals, Aspartic Acid, Carcinoma, Non-Small-Cell Lung, Cell Survival, Cytosol, Drug Synergism, Fluorouracil, Glutaminase, Glutamine, Lung Neoplasms, Malates, Mice, Inbred BALB C, Mice, Nude, NAD, Oxidation-Reduction, Sulfides, Thiadiazoles, Thymidylate Synthase, Cell Death, Glutamic Acid, Xenograft Model Antitumor Assays, Cell Proliferation, Gene Knockdown Techniques, Molecular Targeted Therapy, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
