Open AccessCancer proteome and metabolite changes linked to SHMT2
Author(s) -
Jiefei Tong,
Jonathan R. Krieger,
Paul Taylor,
Richard D. Bagshaw,
Jae Seung Kang,
Swathi P. Jeedigunta,
Leanne Wybenga-Groot,
Wen Zhang,
Heba Badr,
Shideh Mirhadi,
Nhu-An Pham,
Étienne Coyaud,
Man Yu,
Ming Li,
Michael Cabanero,
Brian Raught,
Jason T. Maynes,
Cynthia Hawkins,
MingSound Tsao,
Michael F. Moran
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0237981
Subject(s) - serine hydroxymethyltransferase , gene knockdown , cell growth , biology , biochemistry , glycine , in vivo , microbiology and biotechnology , chemistry , apoptosis , amino acid , genetics
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.