Methionine metabolism in health and cancer: a nexus of diet and precision medicine

Sanderson, Sydney M.; Gao, Xia; Dai, Ziwei; Locasale, Jason W.

doi:10.1038/s41568-019-0187-8

Cited by 305 publications

(247 citation statements)

References 163 publications

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“…These data suggest that the MR-induced inhibition of cancer progression is due, at least in part, to cell-autonomous effects on tumors [12]. There are many alterations in methionine metabolism associated with cancer and understanding how dietary methionine affects cancer could yield important insights into novel treatment approaches [97]. Preclinical studies indicate that MR is effective when implemented in both prevention and treatment contexts and enhances efficacy of some standard cancer therapies.…”

Section: Discussionmentioning

confidence: 98%

Methionine Restriction and Cancer Biology

2020

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The essential amino acid, methionine, is important for cancer cell growth and metabolism. A growing body of evidence indicates that methionine restriction inhibits cancer cell growth and may enhance the efficacy of chemotherapeutic agents. This review summarizes the efficacy and mechanism of action of methionine restriction on hallmarks of cancer in vitro and in vivo. The review highlights the role of glutathione formation, polyamine synthesis, and methyl group donation as mediators of the effects of methionine restriction on cancer biology. The translational potential of the use of methionine restriction as a personalized nutritional approach for the treatment of patients with cancer is also discussed.

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Section: Discussionmentioning

confidence: 98%

Methionine Restriction and Cancer Biology

2020

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“…Many cancer-cell types exhibit an increased requirement for methionine (Vazquez et al 2016). Thus, methionine restriction can potentially be exploited to treat cancers that exhibit methionine dependency, as diet is known to influence methionine metabolism in addition to methionine pathway mutations (Sanderson et al 2019a;. Decreased levels of the media component l-alanyll-glutamine (stable and non-toxic glutamine source) were found for colorectal cancer cells harbouring G13D, G12A, G12D, G12V and G12R mutations compared to their background-matched KRAS wild type cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines

Varshavi

McCarthy

et al. 2020

Metabolomics

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Introduction Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) mutations occur in approximately one-third of colorectal (CRC) tumours and have been associated with poor prognosis and resistance to some therapeutics. In addition to the well-documented pro-tumorigenic role of mutant Ras alleles, there is some evidence suggesting that not all KRAS mutations are equal and the position and type of amino acid substitutions regulate biochemical activity and transforming capacity of KRAS mutations. Objectives To investigate the metabolic signatures associated with different KRAS mutations in codons 12, 13, 61 and 146 and to determine what metabolic pathways are affected by different KRAS mutations. Methods We applied an NMR-based metabonomics approach to compare the metabolic profiles of the intracellular extracts and the extracellular media from isogenic human SW48 CRC cell lines with different KRAS mutations in codons 12 (G12D, G12A, G12C, G12S, G12R, G12V), 13 (G13D), 61 (Q61H) and 146 (A146T) with their wild-type counterpart. We used false discovery rate (FDR)-corrected analysis of variance (ANOVA) to determine metabolites that were statistically significantly different in concentration between the different mutants. Results CRC cells carrying distinct KRAS mutations exhibited differential metabolic remodelling, including differences in glycolysis, glutamine utilization and in amino acid, nucleotide and hexosamine metabolism. Conclusions Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS.

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“…Dietary methionine limitation restricts tumor growth and synergizes with anti-folate therapies in some cancers 40,41 . Methionine is an essential amino acid for mammals, but can be resynthesized from precursors involved in one-carbon and polyamine metabolism 42 . On a wholeanimal level, MTR contributes to methionine re-synthesis; however, animals are capable of maintaining methionine levels via other pathways in the absence of MTR 9 , and we observe that MTR is not critical for maintaining intracellular methionine levels in a cancer cell-autonomous fashion.…”

Section: Discussionmentioning

confidence: 99%

Methionine synthase is essential for cancer cell proliferation in physiological folate environments

Sullivan

Darnell

Reilly

et al. 2020

Preprint

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Targeting folate metabolism can be an effective way to treat cancer. The enzyme methionine synthase catalyzes a key reaction in both folate and methionine metabolism. Early work suggested that inhibiting methionine synthase might restrain tumor growth, though the mechanism remains unclear. We find that due to its specific role in processing folates, methionine synthase is required for cancer proliferation. However, widely used cell culture conditions obscure the proliferative and metabolic consequences of methionine synthase inhibition. Complete dependence on methionine synthase only arises when 5-methyl tetrahydrofolate, the major folate found in circulation, is the predominant folate source provided to cells. In these physiological folate conditions, methionine synthase activity is necessary to maintain intracellular levels of nucleotides, but not methionine. These data reveal that the extracellular environment can alter the essentiality of methionine synthase and suggest that this enzyme plays a crucial cell-autonomous role in supporting nucleotide synthesis and cell proliferation in physiological contexts. Fellowship. A.M.D. was supported by a Jane Coffin Childs Postdoctoral Fellowship. M.G.V.H. acknowledges support from R35CA242379, R01CA201276, the Ludwig Center at MIT, the MIT Center for Precision Cancer Medicine, SU2C, the Emerald Foundation, the Lustgarten Foundation, and a Faculty Scholars Grant from HHMI. AUTHOR CONTRIBUTIONS Conceptualization, M.R.S., M.G.V.H.; Methodology, M.R.S., M.F.R., C.A.L.; Formal Analysis, M.R.S., A.M.D.; Investigation, M.R.S., A.M.D., M.F.R.; Resources, C.A.L.; Visualization, M.R.S., A.M.D.; Writing -Original Draft, M.R.S.; Writing -Review & Editing, M.R.S., A.M.D., M.G.V.H.; Funding Acquisition, M.R.S., A.M.D., M.G.V.H.

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Methionine metabolism in health and cancer: a nexus of diet and precision medicine

Cited by 305 publications

References 163 publications

Methionine Restriction and Cancer Biology

Methionine Restriction and Cancer Biology

Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines

Methionine synthase is essential for cancer cell proliferation in physiological folate environments

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