PMID- 32903271
OWN - NLM
STAT- MEDLINE
DCOM- 20201026
LR  - 20201026
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 15
IP  - 9
DP  - 2020
TI  - Cancer proteome and metabolite changes linked to SHMT2.
PG  - e0237981
LID - 10.1371/journal.pone.0237981 [doi]
LID - e0237981
AB  - 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.
FAU - Tong, Jiefei
AU  - Tong J
AUID- ORCID: 0000-0002-0254-201X
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
FAU - Krieger, Jonathan R
AU  - Krieger JR
AD  - SPARC BioCentre, The Hospital for Sick Children, Toronto, Canada.
FAU - Taylor, Paul
AU  - Taylor P
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
AD  - SPARC BioCentre, The Hospital for Sick Children, Toronto, Canada.
FAU - Bagshaw, Rick
AU  - Bagshaw R
AD  - Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada.
FAU - Kang, Jae
AU  - Kang J
AD  - Department of Molecular Genetics, University of Toronto, Toronto, Canada.
FAU - Jeedigunta, Swathi
AU  - Jeedigunta S
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
AD  - Department of Molecular Genetics, University of Toronto, Toronto, Canada.
FAU - Wybenga-Groot, Leanne E
AU  - Wybenga-Groot LE
AD  - SPARC BioCentre, The Hospital for Sick Children, Toronto, Canada.
FAU - Zhang, Wen
AU  - Zhang W
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
AD  - Department of Molecular Genetics, University of Toronto, Toronto, Canada.
FAU - Badr, Heba
AU  - Badr H
AUID- ORCID: 0000-0002-8238-7928
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
FAU - Mirhadi, Shideh
AU  - Mirhadi S
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
AD  - Department of Molecular Genetics, University of Toronto, Toronto, Canada.
FAU - Pham, Nhu-An
AU  - Pham NA
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
FAU - Coyaud, Etienne
AU  - Coyaud E
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
FAU - Yu, Man
AU  - Yu M
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
FAU - Li, Ming
AU  - Li M
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
FAU - Cabanero, Michael
AU  - Cabanero M
AD  - Department of Laboratory Medicine and Pathobiology, University of Toronto, 
      Toronto, Canada.
FAU - Raught, Brian
AU  - Raught B
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
AD  - Department of Medical Biophysics, University of Toronto, Toronto, Canada.
FAU - Maynes, Jason T
AU  - Maynes JT
AUID- ORCID: 0000-0002-2050-3620
AD  - Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada.
FAU - Hawkins, Cynthia
AU  - Hawkins C
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
FAU - Tsao, Ming Sound
AU  - Tsao MS
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
AD  - Department of Laboratory Medicine and Pathobiology, University of Toronto, 
      Toronto, Canada.
AD  - Department of Medical Biophysics, University of Toronto, Toronto, Canada.
FAU - Moran, Michael F
AU  - Moran MF
AD  - Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
AD  - Department of Molecular Genetics, University of Toronto, Toronto, Canada.
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200909
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antifungal Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Proteome)
RN  - 452VLY9402 (Serine)
RN  - EC 2.1.2.1 (Glycine Hydroxymethyltransferase)
RN  - EC 2.1.2.1 (SHMT protein, human)
RN  - OJ245FE5EU (Sodium Benzoate)
SB  - IM
MH  - Animals
MH  - Antifungal Agents/pharmacology
MH  - Apoptosis
MH  - Biomarkers, Tumor/genetics/*metabolism
MH  - Cell Proliferation
MH  - *Gene Expression Regulation, Neoplastic
MH  - Glycine Hydroxymethyltransferase/antagonists & inhibitors/genetics/*metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Lung Neoplasms/drug therapy/genetics/metabolism/*pathology
MH  - *Metabolome
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Mitochondria/drug effects/metabolism/pathology
MH  - Protein Interaction Domains and Motifs
MH  - Proteome/*analysis
MH  - Serine/*metabolism
MH  - Sodium Benzoate/pharmacology
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
PMC - PMC7480864
COIS- NO authors have competing interests.
EDAT- 2020/09/10 06:00
MHDA- 2020/10/27 06:00
PMCR- 2020/09/09
CRDT- 2020/09/09 17:52
PHST- 2020/03/31 00:00 [received]
PHST- 2020/08/06 00:00 [accepted]
PHST- 2020/09/09 17:52 [entrez]
PHST- 2020/09/10 06:00 [pubmed]
PHST- 2020/10/27 06:00 [medline]
PHST- 2020/09/09 00:00 [pmc-release]
AID - PONE-D-20-07588 [pii]
AID - 10.1371/journal.pone.0237981 [doi]
PST - epublish
SO  - PLoS One. 2020 Sep 9;15(9):e0237981. doi: 10.1371/journal.pone.0237981. 
      eCollection 2020.