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.
Highlights
Glutamine metabolism regulated by cancer-specific glutaminase (EC 3.5.1.2, glutaminase 1 (GLS1), L-glutaminase and glutamine aminohydrolase) has been gaining attention in cancer biology as it has been reported that high levels of kidney-type glutaminase are associated with oncogenic activation
Kaplan–Meier analysis demonstrated that higher than average expression levels in GLS1 and thymidylate synthase (TYMS) gene expression were associated with poorer overall survival
We found that the A549 human lung adenocarcinoma cell line showed selective glutamine dependency for growth compared with the other cancer cells among the metabolic challenges
Summary
High expression of GLS1 inversely correlates with overall survival in NSCLC. In order to perform a survival analysis of NSCLC, we gathered clinical information on lung adenocarcinoma patients from The Cancer Genome Atlas (TCGA).[12]. Reduction of ATP production was about 30% of control by BPTES treatment while other inhibitions reduced about 10% of control ATP production in A549 and EKVX This suggests that the major energy source of NSCLC depends on glutamine instead of glucose or fatty acids. BPTES treatment reduced about 30% ATP production under normoxia, and an additional 10% reduction of ATP production was observed under hypoxia in EKVX (Supplementary Figure 2b) This suggests that GLS1 dependency for ATP production was not changed by the. GLS1 knockdown reduced glutamate levels, and ATP production decreased by up to 40%; GOT2 knockdown resulted in approximately 40% reduction in ATP production (Figure 3c), which suggests that NSCLC depends on the MAS system for ATP supply through NADH transportation.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
