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FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA

Hypoxia is a common feature of glioblastoma, and a known driver of therapy resistance in brain tumours. Understanding the metabolic adaptations to hypoxia is key to develop new effective treatments for patients. A recent screening study highlighted Pyrroline-5-carboxylate reductase-like (PYCRL) as o...

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Autores principales: Vettore, Lisa, Westbrook, Rebecca, Roberts, Jennie, Escribano-Gonzalez, Cristina, Cuozzo, Federica, Hodson, David, Watts, Colin, Nixon, Colin, Tennant, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992204/
http://dx.doi.org/10.1093/noajnl/vdab024.076
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author Vettore, Lisa
Westbrook, Rebecca
Roberts, Jennie
Escribano-Gonzalez, Cristina
Cuozzo, Federica
Hodson, David
Watts, Colin
Nixon, Colin
Tennant, Daniel
author_facet Vettore, Lisa
Westbrook, Rebecca
Roberts, Jennie
Escribano-Gonzalez, Cristina
Cuozzo, Federica
Hodson, David
Watts, Colin
Nixon, Colin
Tennant, Daniel
author_sort Vettore, Lisa
collection PubMed
description Hypoxia is a common feature of glioblastoma, and a known driver of therapy resistance in brain tumours. Understanding the metabolic adaptations to hypoxia is key to develop new effective treatments for patients. A recent screening study highlighted Pyrroline-5-carboxylate reductase-like (PYCRL) as one of the top three genes that allowed tumour survival in hypoxia. PYCRL is one of the three enzymes involved in proline biosynthesis along with the mitochondrial pyrroline-5-carboxylate reductase 1 and 2 (PYCR1/2). The latter use glutamine as the carbon source to fuel the pyrroline-5-carboxylate (P5C)-to-proline reaction, whereas the cytosolic PYCRL is known to use ornithine to produce proline. Our investigations have shown that PYCRL differs from PYCR1 and 2 in the impact on cellular redox, which is a critical factor in hypoxic survival. Our data suggest that PYCRL activity is required for normal regulation of glioblastoma cell growth and the ability to deal with cellular stress, and that this enzyme may therefore represent a novel target in the treatment of these devastating tumours. Importantly, our study also begins to provide much-needed clarity over the network surrounding proline metabolism and redox maintenance.
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spelling pubmed-79922042021-03-31 FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA Vettore, Lisa Westbrook, Rebecca Roberts, Jennie Escribano-Gonzalez, Cristina Cuozzo, Federica Hodson, David Watts, Colin Nixon, Colin Tennant, Daniel Neurooncol Adv Supplement Abstracts Hypoxia is a common feature of glioblastoma, and a known driver of therapy resistance in brain tumours. Understanding the metabolic adaptations to hypoxia is key to develop new effective treatments for patients. A recent screening study highlighted Pyrroline-5-carboxylate reductase-like (PYCRL) as one of the top three genes that allowed tumour survival in hypoxia. PYCRL is one of the three enzymes involved in proline biosynthesis along with the mitochondrial pyrroline-5-carboxylate reductase 1 and 2 (PYCR1/2). The latter use glutamine as the carbon source to fuel the pyrroline-5-carboxylate (P5C)-to-proline reaction, whereas the cytosolic PYCRL is known to use ornithine to produce proline. Our investigations have shown that PYCRL differs from PYCR1 and 2 in the impact on cellular redox, which is a critical factor in hypoxic survival. Our data suggest that PYCRL activity is required for normal regulation of glioblastoma cell growth and the ability to deal with cellular stress, and that this enzyme may therefore represent a novel target in the treatment of these devastating tumours. Importantly, our study also begins to provide much-needed clarity over the network surrounding proline metabolism and redox maintenance. Oxford University Press 2021-03-25 /pmc/articles/PMC7992204/ http://dx.doi.org/10.1093/noajnl/vdab024.076 Text en © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Supplement Abstracts
Vettore, Lisa
Westbrook, Rebecca
Roberts, Jennie
Escribano-Gonzalez, Cristina
Cuozzo, Federica
Hodson, David
Watts, Colin
Nixon, Colin
Tennant, Daniel
FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA
title FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA
title_full FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA
title_fullStr FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA
title_full_unstemmed FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA
title_short FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA
title_sort fsmp-12. a role for proline biosynthesis in hypoxic glioblastoma
topic Supplement Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992204/
http://dx.doi.org/10.1093/noajnl/vdab024.076
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