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Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells

Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and c...

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Autores principales: Alaqbi, Saif Sattar, Burke, Lynsey, Guterman, Inna, Green, Caleb, West, Kevin, Palacios-Gallego, Raquel, Cai, Hong, Alexandrou, Constantinos, Myint, Ni Ni Moe, Parrott, Emma, Howells, Lynne M., Higgins, Jennifer A., Jones, Donald J. L., Singh, Rajinder, Britton, Robert G., Tufarelli, Cristina, Thomas, Anne, Rufini, Alessandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820619/
https://www.ncbi.nlm.nih.gov/pubmed/35130302
http://dx.doi.org/10.1371/journal.pone.0262364
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author Alaqbi, Saif Sattar
Burke, Lynsey
Guterman, Inna
Green, Caleb
West, Kevin
Palacios-Gallego, Raquel
Cai, Hong
Alexandrou, Constantinos
Myint, Ni Ni Moe
Parrott, Emma
Howells, Lynne M.
Higgins, Jennifer A.
Jones, Donald J. L.
Singh, Rajinder
Britton, Robert G.
Tufarelli, Cristina
Thomas, Anne
Rufini, Alessandro
author_facet Alaqbi, Saif Sattar
Burke, Lynsey
Guterman, Inna
Green, Caleb
West, Kevin
Palacios-Gallego, Raquel
Cai, Hong
Alexandrou, Constantinos
Myint, Ni Ni Moe
Parrott, Emma
Howells, Lynne M.
Higgins, Jennifer A.
Jones, Donald J. L.
Singh, Rajinder
Britton, Robert G.
Tufarelli, Cristina
Thomas, Anne
Rufini, Alessandro
author_sort Alaqbi, Saif Sattar
collection PubMed
description Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells’ proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells’ survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.
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spelling pubmed-88206192022-02-08 Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells Alaqbi, Saif Sattar Burke, Lynsey Guterman, Inna Green, Caleb West, Kevin Palacios-Gallego, Raquel Cai, Hong Alexandrou, Constantinos Myint, Ni Ni Moe Parrott, Emma Howells, Lynne M. Higgins, Jennifer A. Jones, Donald J. L. Singh, Rajinder Britton, Robert G. Tufarelli, Cristina Thomas, Anne Rufini, Alessandro PLoS One Research Article Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells’ proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells’ survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies. Public Library of Science 2022-02-07 /pmc/articles/PMC8820619/ /pubmed/35130302 http://dx.doi.org/10.1371/journal.pone.0262364 Text en © 2022 Alaqbi et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Alaqbi, Saif Sattar
Burke, Lynsey
Guterman, Inna
Green, Caleb
West, Kevin
Palacios-Gallego, Raquel
Cai, Hong
Alexandrou, Constantinos
Myint, Ni Ni Moe
Parrott, Emma
Howells, Lynne M.
Higgins, Jennifer A.
Jones, Donald J. L.
Singh, Rajinder
Britton, Robert G.
Tufarelli, Cristina
Thomas, Anne
Rufini, Alessandro
Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells
title Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells
title_full Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells
title_fullStr Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells
title_full_unstemmed Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells
title_short Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells
title_sort increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820619/
https://www.ncbi.nlm.nih.gov/pubmed/35130302
http://dx.doi.org/10.1371/journal.pone.0262364
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