Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion

Koufaris, Costas; Gallage, Suchira; Yang, Tianlai; Lau, Chung-Ho E; Valbuena, Gabriel N.; Keun, Hector C.

doi:10.1021/acs.jproteome.6b00188

Cited by 39 publications

(32 citation statements)

References 29 publications

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“…Although moleculartargeted therapy can offer significant clinical benefits for metastatic RCC, its effectiveness eventually declines with the development of resistance [27]. Recently, it was found that MTHFD2 suppression may increase the sensitivity of breast cancer cells to folate depletion [28]. Our study is consistent with this report, as the loss of MTHFD2 increased the sensitivity of 786-O cells to chemotherapy drugs.…”

Section: Mthfd2 Down-regulation Sensitizes 786-o Cells To Chemotherapsupporting

confidence: 91%

MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion

Lin

Huang

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: To investigate the role of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in the clinical prognosis and cell biology of renal cell carcinoma (RCC). Methods: A total of 137 RCC tissues were evaluated by immunohistochemistry. The relationship between MTHFD2 overexpression and clinical parameters and vimentin expression was assessed. Kaplan-Meier curves and the log-rank test were applied for survival analysis according to MTHFD2 and vimentin expression in RCC tissues. The expression of MTHFD2 mRNA and protein was examined by quantitative reverse transcription PCR and western blotting, respectively. To determine further the biological activity of MTHFD2 in RCC, 786-O cells were transfected with short hairpin RNA specifically targeting MTHFD2 (shMTHFD2) with or without tumor necrosis factor (TNF)-α stimulation. Cell proliferation, cell migration and invasion and drug sensitivity were subsequently assessed using Cell Counting Kit-8, wound healing, and Transwell assays. Results: Immunohistochemical analysis demonstrated that both MTHFD2 and vimentin overexpression was positively associated with clinical staging, pathological grade, and poor overall survival (all P < 0.05). MTHFD2 expression was closely correlated with vimentin overexpression in RCC (r = 0.402, P < 0.001). After knocking down MTHFD2 expression in 786-O cells, decreased cell proliferation, migration, and invasion were observed and accompanied by the reduced expression of vimentin. The effects of MTHFD2 down-regulation could be partially restrained by TNF-α treatment. Vimentin expression and cell migration and invasion, but not cell proliferation, were reversed by TNF-α stimulation. Furthermore, treatment of 786-O cells with shMTHFD2 increased their sensitivity to chemotherapy drugs. Conclusion: The current results demonstrated that MTHFD2 was overexpressed in RCC and associated with poor clinical characteristics, vimentin expression, and cellular features connected to malignant disease, thus, implicating MTHFD2 as a potential target for RCC therapy.

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Section: Mthfd2 Down-regulation Sensitizes 786-o Cells To Chemotherapsupporting

confidence: 91%

MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion

Lin

Huang

Wang

et al. 2018

Cell Physiol Biochem

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“…2N). Work from another group has shown that knockdown of MTHFD2 also results in increased lactate release in the MCF7 breast cancer cells ( 19 ). Together, the lack of any phenotype regarding purine levels and growth in MTHFD1L knockdown cells, but an increase in glycolysis, suggests a catabolic rather than an anabolic role of the serine one-carbon catabolism to glycine and formate.…”

Section: Resultsmentioning

confidence: 99%

Serine one-carbon catabolism with formate overflow

et al. 2016

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“…Increased MTHFD2 expression is associated with acute myeloid leukemia, breast cancer, lung cancer, and liver cancer [ 14 – 20 ], and MTHFD2 is considered a novel target for anticancer therapy [ 21 , 22 ]. A number of recent studies have shown that the mitochondrial 1C pathway is often reprogrammed in cancer cells and is especially critical for maintaining NADPH/NADP + redox homeostasis [ 19 , 23 – 27 ]. MTHFD2 is generally regarded as the enzyme responsible for this mitochondrial NADPH production, although ALDH1L2 has also been invoked [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

2017

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BackgroundFolate-dependent one-carbon metabolism provides one-carbon units for several biological processes. This pathway is highly compartmentalized in eukaryotes, with the mitochondrial pathway producing formate for use in cytoplasmic processes. The mitochondrial enzyme MTHFD2 has been reported to use NAD+ as a cofactor while the isozyme MTHFD2L utilizes NAD+ or NADP+ at physiologically relevant conditions. Because MTHFD2 is highly expressed in many cancer types, we sought to determine the cofactor preference of this enzyme.ResultsKinetic analysis shows that purified human MTHFD2 exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+ with the more physiologically relevant pentaglutamate folate substrate.ConclusionThese results show that the mitochondrial folate pathway isozymes MTHFD2 and MTHFD2L both exhibit dual redox cofactor specificity. Our kinetic analysis clearly supports a role for MTHFD2 in mitochondrial NADPH production, indicating that this enzyme is likely responsible for mitochondrial production of both NADH and NADPH in rapidly proliferating cells.

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Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion

Cited by 39 publications

References 29 publications

MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion

MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion

Serine one-carbon catabolism with formate overflow

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

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