Cargando…
The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling
BACKGROUND: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations inc...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920530/ https://www.ncbi.nlm.nih.gov/pubmed/33681764 http://dx.doi.org/10.1093/noajnl/vdaa149 |
_version_ | 1783658295468228608 |
---|---|
author | Yamashita, Alex Shimura da Costa Rosa, Marina Stumpo, Vittorio Rais, Rana Slusher, Barbara S Riggins, Gregory J |
author_facet | Yamashita, Alex Shimura da Costa Rosa, Marina Stumpo, Vittorio Rais, Rana Slusher, Barbara S Riggins, Gregory J |
author_sort | Yamashita, Alex Shimura |
collection | PubMed |
description | BACKGROUND: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. MATERIAL AND METHODS: We performed cell growth, cell cycle, and protein expression in glutamine deprived or Glutaminase (GLS) gene silenced glioma cells. We tested the effect of JHU-083 on cell proliferation, metabolism, and mTOR signaling in cancer cell lines. An orthotopic IDH1R132H glioma model was used to test the efficacy of JHU-083 in vivo. RESULTS: Glutamine deprivation and GLS gene silencing reduced glioma cell proliferation in vitro in glioma cells. JHU-083 reduced glioma cell growth in vitro, modulated cell metabolism, and disrupted mTOR signaling and downregulated Cyclin D1 protein expression, through a mechanism independent of TSC2 modulation and glutaminolysis. IDH1R132H isogenic cells preferentially reduced cell growth and mTOR signaling downregulation. In addition, guanine supplementation partially rescued IDHmut glioma cell growth, mTOR signaling, and Cyclin D1 protein expression in vitro. Finally, JHU-083 extended survival in an intracranial IDH1 mut glioma model and reduced intracranial pS6 protein expression. CONCLUSION: Targeting glutamine metabolism with JHU-083 showed efficacy in preclinical models of IDHmut glioma and measurably decreased mTOR signaling. |
format | Online Article Text |
id | pubmed-7920530 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-79205302021-03-04 The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling Yamashita, Alex Shimura da Costa Rosa, Marina Stumpo, Vittorio Rais, Rana Slusher, Barbara S Riggins, Gregory J Neurooncol Adv Basic and Translational Investigations BACKGROUND: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. MATERIAL AND METHODS: We performed cell growth, cell cycle, and protein expression in glutamine deprived or Glutaminase (GLS) gene silenced glioma cells. We tested the effect of JHU-083 on cell proliferation, metabolism, and mTOR signaling in cancer cell lines. An orthotopic IDH1R132H glioma model was used to test the efficacy of JHU-083 in vivo. RESULTS: Glutamine deprivation and GLS gene silencing reduced glioma cell proliferation in vitro in glioma cells. JHU-083 reduced glioma cell growth in vitro, modulated cell metabolism, and disrupted mTOR signaling and downregulated Cyclin D1 protein expression, through a mechanism independent of TSC2 modulation and glutaminolysis. IDH1R132H isogenic cells preferentially reduced cell growth and mTOR signaling downregulation. In addition, guanine supplementation partially rescued IDHmut glioma cell growth, mTOR signaling, and Cyclin D1 protein expression in vitro. Finally, JHU-083 extended survival in an intracranial IDH1 mut glioma model and reduced intracranial pS6 protein expression. CONCLUSION: Targeting glutamine metabolism with JHU-083 showed efficacy in preclinical models of IDHmut glioma and measurably decreased mTOR signaling. Oxford University Press 2020-10-29 /pmc/articles/PMC7920530/ /pubmed/33681764 http://dx.doi.org/10.1093/noajnl/vdaa149 Text en © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Basic and Translational Investigations Yamashita, Alex Shimura da Costa Rosa, Marina Stumpo, Vittorio Rais, Rana Slusher, Barbara S Riggins, Gregory J The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling |
title | The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling |
title_full | The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling |
title_fullStr | The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling |
title_full_unstemmed | The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling |
title_short | The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling |
title_sort | glutamine antagonist prodrug jhu-083 slows malignant glioma growth and disrupts mtor signaling |
topic | Basic and Translational Investigations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920530/ https://www.ncbi.nlm.nih.gov/pubmed/33681764 http://dx.doi.org/10.1093/noajnl/vdaa149 |
work_keys_str_mv | AT yamashitaalexshimura theglutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT dacostarosamarina theglutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT stumpovittorio theglutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT raisrana theglutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT slusherbarbaras theglutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT rigginsgregoryj theglutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT yamashitaalexshimura glutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT dacostarosamarina glutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT stumpovittorio glutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT raisrana glutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT slusherbarbaras glutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling AT rigginsgregoryj glutamineantagonistprodrugjhu083slowsmalignantgliomagrowthanddisruptsmtorsignaling |