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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Jonathan Krieger

LAB HEAD: Michael F Moran

PROVIDER: PXD004954 | Pride | 2020-08-19

REPOSITORIES: Pride

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Project description:Triple-negative breast cancer (TNBC) is defined as pathologically negative for estrogen receptor α (ER-), progesterone receptor (PR-), and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy, recently supplemented by immunotherapy [37296893]. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including gamma secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs. We confirmed that SS, a known gamma secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, the anti-tumor effects of SS were significantly enhanced when combined with α-PD1 immunotherapy in our TNBC organoids and in vivo. Our data support further investigation of SS for the treatment of TNBC, in conjunction with standard of care chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option solution for a patient population in need of effective therapies.

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

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