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Cancer proteome and metabolite changes linked to SHMT2

Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible ove...

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Autores principales: Tong, Jiefei, Krieger, Jonathan R., Taylor, Paul, Bagshaw, Rick, Kang, Jae, Jeedigunta, Swathi, Wybenga-Groot, Leanne E., Zhang, Wen, Badr, Heba, Mirhadi, Shideh, Pham, Nhu-An, Coyaud, Étienne, Yu, Man, Li, Ming, Cabanero, Michael, Raught, Brian, Maynes, Jason T., Hawkins, Cynthia, Tsao, Ming Sound, Moran, Michael F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480864/
https://www.ncbi.nlm.nih.gov/pubmed/32903271
http://dx.doi.org/10.1371/journal.pone.0237981
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author Tong, Jiefei
Krieger, Jonathan R.
Taylor, Paul
Bagshaw, Rick
Kang, Jae
Jeedigunta, Swathi
Wybenga-Groot, Leanne E.
Zhang, Wen
Badr, Heba
Mirhadi, Shideh
Pham, Nhu-An
Coyaud, Étienne
Yu, Man
Li, Ming
Cabanero, Michael
Raught, Brian
Maynes, Jason T.
Hawkins, Cynthia
Tsao, Ming Sound
Moran, Michael F.
author_facet Tong, Jiefei
Krieger, Jonathan R.
Taylor, Paul
Bagshaw, Rick
Kang, Jae
Jeedigunta, Swathi
Wybenga-Groot, Leanne E.
Zhang, Wen
Badr, Heba
Mirhadi, Shideh
Pham, Nhu-An
Coyaud, Étienne
Yu, Man
Li, Ming
Cabanero, Michael
Raught, Brian
Maynes, Jason T.
Hawkins, Cynthia
Tsao, Ming Sound
Moran, Michael F.
author_sort Tong, Jiefei
collection PubMed
description Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function.
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spelling pubmed-74808642020-09-18 Cancer proteome and metabolite changes linked to SHMT2 Tong, Jiefei Krieger, Jonathan R. Taylor, Paul Bagshaw, Rick Kang, Jae Jeedigunta, Swathi Wybenga-Groot, Leanne E. Zhang, Wen Badr, Heba Mirhadi, Shideh Pham, Nhu-An Coyaud, Étienne Yu, Man Li, Ming Cabanero, Michael Raught, Brian Maynes, Jason T. Hawkins, Cynthia Tsao, Ming Sound Moran, Michael F. PLoS One Research Article Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function. Public Library of Science 2020-09-09 /pmc/articles/PMC7480864/ /pubmed/32903271 http://dx.doi.org/10.1371/journal.pone.0237981 Text en © 2020 Tong et al 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 use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tong, Jiefei
Krieger, Jonathan R.
Taylor, Paul
Bagshaw, Rick
Kang, Jae
Jeedigunta, Swathi
Wybenga-Groot, Leanne E.
Zhang, Wen
Badr, Heba
Mirhadi, Shideh
Pham, Nhu-An
Coyaud, Étienne
Yu, Man
Li, Ming
Cabanero, Michael
Raught, Brian
Maynes, Jason T.
Hawkins, Cynthia
Tsao, Ming Sound
Moran, Michael F.
Cancer proteome and metabolite changes linked to SHMT2
title Cancer proteome and metabolite changes linked to SHMT2
title_full Cancer proteome and metabolite changes linked to SHMT2
title_fullStr Cancer proteome and metabolite changes linked to SHMT2
title_full_unstemmed Cancer proteome and metabolite changes linked to SHMT2
title_short Cancer proteome and metabolite changes linked to SHMT2
title_sort cancer proteome and metabolite changes linked to shmt2
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480864/
https://www.ncbi.nlm.nih.gov/pubmed/32903271
http://dx.doi.org/10.1371/journal.pone.0237981
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