title: Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC.
abstract: 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.
authors.affiliation: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.|Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Joon H
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.|Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Seon-Hyeong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Dongwan
authors.identifier: 0000-0002-7816-1299
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jaekyoung
authors.identifier: 0000-0001-8152-9210
authors.initials: J
authors.lastname: Son
authors.affiliation: Omics Core Laboratory, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Kyeong M
authors.initials: KM
authors.lastname: Hong
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Jaewhan
authors.initials: J
authors.lastname: Song
authors.affiliation: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Soo-Youl
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000072283:A549 Cells; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D008293:Malates / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D013440:Sulfides / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D008293:Malates; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005973:Glutamine; D009243:NAD; D001224:Aspartic Acid; D018698:Glutamic Acid; C030298:malic acid; D000255:Adenosine Triphosphate; D013940:Thymidylate Synthase; D005972:Glutaminase; D005472:Fluorouracil