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Nutrients Mar 2020The essential amino acid, methionine, is important for cancer cell growth and metabolism. A growing body of evidence indicates that methionine restriction inhibits... (Review)
Review
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.
Topics: Animals; Humans; Methionine; Neoplasms
PubMed: 32138282
DOI: 10.3390/nu12030684 -
Ageing Research Reviews Jun 2023The restriction of calories, branched-chain amino acids, and methionine have all been shown to extend lifespan in model organisms. Recently, glycine was found to boost... (Review)
Review
The restriction of calories, branched-chain amino acids, and methionine have all been shown to extend lifespan in model organisms. Recently, glycine was found to boost longevity in genetically heterogenous mice. This simple amino acid similarly extends lifespan in rats and improves health in mammalian models of age-related disease. While compelling data indicate that glycine is a pro-longevity molecule, divergent mechanisms may underlie its effects on aging. Glycine is abundant in collagen, a building block for glutathione, a precursor to creatine, and an acceptor for the enzyme glycine N-methyltransferase (GNMT). A review of the literature strongly implicates GNMT, which clears methionine from the body by taking a methyl group from S-adenosyl-L-methionine and methylating glycine to form sarcosine. In flies, Gnmt is required for reduced insulin/insulin-like growth factor 1 signaling and dietary restriction to fully extend lifespan. The geroprotector spermidine requires Gnmt to upregulate autophagy genes and boost longevity. Moreover, the overexpression of Gnmt is sufficient to extend lifespan and reduce methionine levels. Sarcosine, or methylglycine, declines with age in multiple species and is capable of inducing autophagy both in vitro and in vivo. Taken all together, existing evidence suggests that glycine prolongs life by mimicking methionine restriction and activating autophagy.
Topics: Rats; Animals; Mice; Humans; Glycine; Sarcosine; Aging; Methionine; Longevity; Glycine N-Methyltransferase; Racemethionine; Mammals
PubMed: 37004845
DOI: 10.1016/j.arr.2023.101922 -
Gut Mar 2023Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether...
OBJECTIVE
Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined.
DESIGN
The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated.
RESULTS
We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8 T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N-methyladenosine (mA) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or mA-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8 T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients.
CONCLUSIONS
Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.
Topics: Mice; Animals; Methionine; CD8-Positive T-Lymphocytes; Methylation; Programmed Cell Death 1 Receptor; Neoplasms; Racemethionine
PubMed: 35803704
DOI: 10.1136/gutjnl-2022-326928 -
Nature Communications Mar 2023Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of...
Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.
Topics: Humans; Animals; Mice; Methionine; Cysteine; Ferroptosis; Proteomics; Racemethionine; Glioma
PubMed: 36864031
DOI: 10.1038/s41467-023-36630-w -
Blood Nov 2022Targeting altered tumor cell metabolism might provide an attractive opportunity for patients with acute myeloid leukemia (AML). An amino acid dropout screen on primary...
Targeting altered tumor cell metabolism might provide an attractive opportunity for patients with acute myeloid leukemia (AML). An amino acid dropout screen on primary leukemic stem cells and progenitor populations revealed a number of amino acid dependencies, of which methionine was one of the strongest. By using various metabolite rescue experiments, nuclear magnetic resonance-based metabolite quantifications and 13C-tracing, polysomal profiling, and chromatin immunoprecipitation sequencing, we identified that methionine is used predominantly for protein translation and to provide methyl groups to histones via S-adenosylmethionine for epigenetic marking. H3K36me3 was consistently the most heavily impacted mark following loss of methionine. Methionine depletion also reduced total RNA levels, enhanced apoptosis, and induced a cell cycle block. Reactive oxygen species levels were not increased following methionine depletion, and replacement of methionine with glutathione or N-acetylcysteine could not rescue phenotypes, excluding a role for methionine in controlling redox balance control in AML. Although considered to be an essential amino acid, methionine can be recycled from homocysteine. We uncovered that this is primarily performed by the enzyme methionine synthase and only when methionine availability becomes limiting. In vivo, dietary methionine starvation was not only tolerated by mice, but also significantly delayed both cell line and patient-derived AML progression. Finally, we show that inhibition of the H3K36-specific methyltransferase SETD2 phenocopies much of the cytotoxic effects of methionine depletion, providing a more targeted therapeutic approach. In conclusion, we show that methionine depletion is a vulnerability in AML that can be exploited therapeutically, and we provide mechanistic insight into how cells metabolize and recycle methionine.
Topics: Mice; Animals; Methionine; Leukemia, Myeloid, Acute; S-Adenosylmethionine; Histones; Racemethionine
PubMed: 35984907
DOI: 10.1182/blood.2022017575 -
Nature Communications Aug 2023Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer, while their effects on ferroptosis-targeting therapy and...
Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer, while their effects on ferroptosis-targeting therapy and immunotherapy are unknown. Here we show the length of time methionine deprivation affects tumoral ferroptosis differently. Prolonged methionine deprivation prevents glutathione (GSH) depletion from exceeding the death threshold by blocking cation transport regulator homolog 1 (CHAC1) protein synthesis. Whereas, short-term methionine starvation accelerates ferroptosis by stimulating CHAC1 transcription. In vivo, dietary methionine with intermittent but not sustained deprivation augments tumoral ferroptosis. Intermittent methionine deprivation also sensitizes tumor cells against CD8 T cell-mediated cytotoxicity and synergize checkpoint blockade therapy by CHAC1 upregulation. Clinically, tumor CHAC1 correlates with clinical benefits and improved survival in cancer patients treated with checkpoint blockades. Lastly, the triple combination of methionine intermittent deprivation, system x inhibitor and PD-1 blockade shows superior antitumor efficacy. Thus, intermittent methionine deprivation is a promising regimen to target ferroptosis and augment cancer immunotherapy.
Topics: Humans; Ferroptosis; Methionine; Apoptosis; Racemethionine; Immunotherapy; Cell Line, Tumor
PubMed: 37553341
DOI: 10.1038/s41467-023-40518-0 -
Nature Genetics Dec 2022Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized...
Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.
Topics: Humans; Child; Glioma; Histones; Methionine; Mutation; Racemethionine; Tumor Microenvironment
PubMed: 36471067
DOI: 10.1038/s41588-022-01236-3 -
Nature Metabolism Sep 2023Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several...
Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system.
Topics: Male; Mice; Female; Animals; Methionine; Hydrogen Sulfide; Gastrointestinal Microbiome; Racemethionine; Neoplasms; Sulfur
PubMed: 37537369
DOI: 10.1038/s42255-023-00854-3 -
Nature Communications May 2023Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T...
Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion.
Topics: Animals; Female; Mice; AMP-Activated Protein Kinases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Methionine; Mice, Knockout; Neoplasms; Programmed Cell Death 1 Receptor; Racemethionine; Up-Regulation
PubMed: 37147330
DOI: 10.1038/s41467-023-38316-9 -
Aging Cell Dec 2019Methionine restriction (MetR) extends lifespan across different species and exerts beneficial effects on metabolic health and inflammatory responses. In contrast,... (Review)
Review
Methionine restriction (MetR) extends lifespan across different species and exerts beneficial effects on metabolic health and inflammatory responses. In contrast, certain cancer cells exhibit methionine auxotrophy that can be exploited for therapeutic treatment, as decreasing dietary methionine selectively suppresses tumor growth. Thus, MetR represents an intervention that can extend lifespan with a complementary effect of delaying tumor growth. Beyond its function in protein synthesis, methionine feeds into complex metabolic pathways including the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Manipulation of each of these branches extends lifespan; however, the interplay between MetR and these branches during regulation of lifespan is not well understood. In addition, a potential mechanism linking the activity of methionine metabolism and lifespan is regulation of production of the methyl donor S-adenosylmethionine, which, after transferring its methyl group, is converted to S-adenosylhomocysteine. Methylation regulates a wide range of processes, including those thought to be responsible for lifespan extension by MetR. Although the exact mechanisms of lifespan extension by MetR or methionine metabolism reprogramming are unknown, it may act via reducing the rate of translation, modifying gene expression, inducing a hormetic response, modulating autophagy, or inducing mitochondrial function, antioxidant defense, or other metabolic processes. Here, we review the mechanisms of lifespan extension by MetR and different branches of methionine metabolism in different species and the potential for exploiting the regulation of methyltransferases to delay aging.
Topics: Aging; Animals; Humans; Longevity; Methionine; Methyltransferases; Species Specificity
PubMed: 31460700
DOI: 10.1111/acel.13034