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B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease.

ABSTRACT: Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.

SUBMITTER: Lyon P

PROVIDER: S-EPMC7551072 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease.

Lyon Peter P Strippoli Victoria V Fang Byron B Cimmino Luisa L

Nutrients 20200919 9

Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to ca ...[more]

PMID: 32961717

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Project description:BackgroundLung cancer remains the major cause of cancer related death worldwide. The discovery of targeted therapies against activating mutations in genes like EGFR considerably improved the prognosis for a subgroup of patients but still leaves a large part without a targeted therapy. One carbon metabolism (1CM) has been investigated in several cancer entities and its increased activity has been linked to higher tumor aggressiveness and reduced prognosis. In spite of 1CM enzymes role and correlation to cancer cells progression, comprehensive analysis for the diagnostic and functional role of the complete 1CM enzymes in lung cancer has not been conducted so far.MethodsWe investigated the prognostic and functional relevance of five major 1CM factors (MTHFD2, PGDH3, SHMT2, MTHFD1 and TYMS) in the three major subclasses of lung cancer [pulmonary adenocarcinoma (AC), squamous cell lung cancer (SQCLC) and small cell lung cancer (SCLC)]. We analyzed 1CM enzymes expression and clinicopathological correlation in patient derived tissue samples of 103 AC, 183 SQCLC and 37 SCLC patients by immunohistochemistry. Furthermore, the effect of 1CM enzymes expression on lung cancer cell proliferation and the response to chemotherapy was investigated in 15 representative AC, SQCLC and SCLC cell lines.ResultsExpression of MTHFD2 and PGDH3 was significantly correlated to a worse overall survival only in AC patients. Cell proliferation assays resolved that all 1CM enzymes have a significant impact on cell growth in AC cell lines and are partially involved in cell proliferation in SQCLC and SCLC cell lines. In addition, expression of MTHFD2 correlated significantly with an increased pemetrexed chemoresistance.ConclusionsExpression of MTHFD2 significantly reduces the prognosis of AC patients. Furthermore, MTHFD2 expression is crucial for survival of AC cell lines and its expression correlates with resistance against Pemetrexed. As MTHFD2 is almost not expressed in healthy adult tissue, we therefore suggest that the inhibition of MTHFD2 might be a potential therapeutic strategy to surround pemetrexed resistance in AC.

Dataset Information

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease.

Publications

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease.

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