Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC

Jae Seon Lee, Joon H. Kang, Seon Hyeong Lee, Dongwan Hong, Jaekyoung Son, Kyeong M. Hong, Jaewhan Song, Soo Youl Kim

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Article numbere2511
JournalCell Death and Disease
Volume7
Issue number12
DOIs
Publication statusPublished - 2016 Jan 1

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Glutaminase
Thymidylate Synthase
Non-Small Cell Lung Carcinoma
Adenosine Triphosphate
Cell Cycle Checkpoints
Aspartic Acid
Fluorouracil
NAD
Glutamic Acid
Cell Death
Malate Dehydrogenase
Sulfides
Group Psychotherapy
Aspartate Aminotransferases
Heterografts
Cytosol
Small Interfering RNA
Glutathione
Reactive Oxygen Species
Mitochondria

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Lee, J. S., Kang, J. H., Lee, S. H., Hong, D., Son, J., Hong, K. M., ... Kim, S. Y. (2016). Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC. Cell Death and Disease, 7(12), [e2511]. https://doi.org/10.1038/cddis.2016.404
Lee, Jae Seon ; Kang, Joon H. ; Lee, Seon Hyeong ; Hong, Dongwan ; Son, Jaekyoung ; Hong, Kyeong M. ; Song, Jaewhan ; Kim, Soo Youl. / Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC. In: Cell Death and Disease. 2016 ; Vol. 7, No. 12.
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Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC. / Lee, Jae Seon; Kang, Joon H.; Lee, Seon Hyeong; Hong, Dongwan; Son, Jaekyoung; Hong, Kyeong M.; Song, Jaewhan; Kim, Soo Youl.

In: Cell Death and Disease, Vol. 7, No. 12, e2511, 01.01.2016.

Research output: Contribution to journalArticle

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