title: Glutaminase 1 inhibition reduces thymidine synthesis in NSCLC.
abstract: We found that non-small cell lung cancer (NSCLC) is remarkably sensitive to the regulation of glutamine supply by testing the metabolic dependency of 11 cancer cell lines against regulation of glycolysis, autophagy, fatty acid synthesis, and glutamine supply. Glutamine is known as a key supplement of cancer cell growth that is converted to α-ketoglutarate for anabolic biogenesis via glutamate by glutaminase 1 (GLS1). GLS1 inhibition using 10 μM of bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) showed about 50% cell growth arrest by SRB assay. By testing the synergistic effects of conventional therapeutics, BPTES combined with 5-fluorouracil (5-FU), an irreversible inhibitor of thymidylate synthase, significant effects were observed on cell growth arrest in NSCLC. We found that GLS1 inhibition using BPTES reduced metabolic intermediates including thymidine and carbamoyl phosphate. Reduction of thymidine and carbamoyl-phosphate synthesis by BPTES treatment exacerbated pyrimidine supply by combination with 5-FU, which induced cell death synergistically in NSCLC.
authors.affiliation: Cancer Cell & Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Cancer Cell & 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 & Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Seon-Hyeong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Cancer Cell & Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Chang-Hun
authors.initials: CH
authors.lastname: Lee
authors.affiliation: University of Ulsan College of Medicine, Department of Biomedical Sciences, Seoul 138-736, Republic of Korea.
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
authors.affiliation: Cancer Cell & Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea. Electronic address: kimsooyoul@gmail.com.
authors.forename: Soo-Youl
authors.initials: SY
authors.lastname: Kim
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D005972:Glutaminase / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism*; D013936:Thymidine / Q000096:biosynthesis*
chemical_list: D005972:Glutaminase; D013936:Thymidine
keywords: 5-fluorouracil; Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide; Cancer metabolism; Glutaminase 1; Non-small cell lung cancer