Cited by 24Cancer, Hypoxia, and MetabolismAmino Acid Enzymes and MetabolismCancer, Lipids, and Metabolism

Cancer proteome and metabolite changes linked to SHMT2

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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.·2020·PLoS ONE

Abstract

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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Authors
Tong, J., Krieger, J. R., Taylor, P., Bagshaw, R., Kang, J., Jeedigunta, S., Wybenga-Groot, L. E., Zhang, W., Badr, H., Mirhadi, S., Pham, N.-A., Coyaud, É., Yu, M., Li, M., Cabanero, M., Raught, B., Maynes, J. T., Hawkins, C., Tsao, M. S., & Moran, M. F.
Affiliations
  • Hospital for Sick Children (CA)
  • University of Toronto (CA)
  • University Health Network (CA)
Corresponding author
Moran, Michael F.
Venue
PLoS ONE
Published
2020-09-09
Volume
15
Issue
9
Pages
e0237981
ISSN
1932-6203 (ISSN-L)
OpenAlex
W3084390693
Cited by
24
References
57
Citations by year
2026: 2 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 6
FWCI
1.37
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • LillOA (Université de Lille (University Of Lille)) (submittedVersion, cc-by)
Funders
  • Genome Canada
  • Hospital for Sick Children
  • Scheme for Promotion of Academic and Research Collaboration
  • Garron Family Cancer Centre
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
SHMT2, cancer metabolism, folate metabolism, AICAR, purine nucleotide synthesis, benzoate, cell proliferation, tumor growth, mitochondrial proteins, protein-protein interaction, HeLa cells, tumor xenografts, proteome changes, metabolite changes
MeSH terms
Animals, Antifungal Agents, HeLa Cells, Humans, Lung Neoplasms, Mitochondria, Serine, Glycine Hydroxymethyltransferase, Tumor Cells, Cultured, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Mice, SCID, Mice, Inbred NOD, Apoptosis, Sodium Benzoate, Proteome, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Protein Interaction Domains and Motifs, Metabolome

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