Proteomics and metabolomics reveal changes in cancer cells after alternation of SHMT2 expressions

In order to understand the underline mechanism of SHMT2 (serine hydroxymethyltransferase 2) effect on tumor growth, proteome and metabolome analysis were carried on a engineered HeLa cell line (HeLa-SHMT2-shSHMT2, short as HeLa-Ss), which has inducible SHMT2 over-expression or suppression by treating cell with tetracycline or IPTG, respectively. SHMT2 over-expression in HeLa-ss cell increased cell proliferation in vitro and in vivo, deceased expression of several mitochondrial complex I and III proteins, and increased glycine and glutathione levels in cells. BioID method identified more than 20 SHMT2 associated proteins that are involved in oxidation-reduction process. These results indicate SHMT2 involves in the regulation of cellular redox balance. SHMT2 repression only reduced growth of cells under glycine depletion condition. It increased expression of several proteins involved in glutaminolysis and amino acid transporters, and elevated metabolites related to glutamine metabolism. These results indicate tumor cells have a compensatory reaction after SHMT2 suppression. Further reducing glycine levels in cells by sodium benzoate caused cell death in cultured cell and slightly reduced tumor growth in vivo. Benzoate treatment induces more changes in protein expressions and metabolite levels and may be a new approach to inhibit tumor growth.