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Modulation of dietary methionine intake elicits potent, but distinct, anticancer effects on primary vs metastatic tumors

ABSTRACT: Methionine concentration in diet influences the growth rate of metastatic cells in vivo

ORGANISM(S): Mus musculus

PROVIDER: GSE111559 | GEO | 2018/03/09

REPOSITORIES: GEO

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Modulation of dietary methionine intake elicits potent, yet distinct, anticancer effects on primary versus metastatic tumors.

Project description:Methionine dependency describes the characteristic rapid in vitro death of most tumor cells in the absence of methionine. Combining chemotherapy with dietary methionine deprivation [methionine-deficient diet (MDD)] at tolerable levels has vast potential in tumor treatment; however, it is limited by MDD-induced toxicity during extended deprivation. Recent advances in imaging and irradiation delivery have created the field of stereotactic body radiotherapy (SBRT), where fewer large-dose fractions delivered in less time result in increased local-tumor control, which could be maximally synergistic with an MDD short course. Identification of the lowest effective methionine dietary intake not associated with toxicity will further enhance the cancer therapy potential. In this study, we investigated the effects of MDD and methionine-restricted diet (MRD) in primary and metastatic melanoma models in combination with radiotherapy (RT). In vitro, MDD dose-dependently sensitized mouse and human melanoma cell lines to RT. In vivo in mice, MDD substantially potentiated the effects of RT by a significant delay in tumor growth, in comparison with administering MDD or RT alone. The antitumor effects of an MDD/RT approach were due to effects on one-carbon metabolism, resulting in impaired methionine biotransformation via downregulation of Mat2a, which encodes methionine adenosyltransferase 2A. Furthermore, and probably most importantly, MDD and MRD substantially diminished metastatic potential; the antitumor MRD effects were not associated with toxicity to normal tissue. Our findings suggest that modulation of methionine intake holds substantial promise for use with short-course SBRT for cancer treatment.

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Modulation of dietary methionine intake elicits potent, but distinct, anticancer effects on primary vs metastatic tumors

Project description:Modulation of dietary methionine intake elicits potent, but distinct, anticancer effects on primary vs metastatic tumors

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Dietary methionine starvation impairs acute myeloid leukemia progression

Project description: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, NMR-based metabolite quantifications and 13C-tracing, polysomal profiling, and ChIP-seq, 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. ROS 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.

2022-12-21 | GSE220236 | GEO

Dietary methionine restriction impairs anti-tumor immunity through gut microbiota

Project description:Dietary methionine restriction represses growth and improves therapeutic responses in several pre-clinical settings. However, how this dietary intervention impacts cancer progression in the context of the immune system is unknown. Here we analyzed the CD45+ immune cells from the small intestine of control (CTRL) diet or methionine-restricted (MR) diet fed tumor-free C57BL/6J donor mice and tumor-bearing Apc <min+/-> recipient mice transplanated with feces from these diet-fed tumor-free C57BL/6J mice by scRNA-seq. Our analysis indicate that fecal microbes from methionine-restricted tumor-free C57BL/6J mice are sufficient to represss T cell activation in the small intestine of Apc <min+/-> mice.

2023-06-14 | GSE181220 | GEO

Effects of 20 months Dietary Methionine Restriction on Hepatic Gene Expression in Fischer 344 Rats

Project description:Dietary methionine restriction (MR) has been shown to increase lifespan and decrease adiposity in rodents. This study was designed to examine the transcriptional effects of MR in metabolically relevant tissues. This experiment contains data from the liver. We analyzed MR-induced changes in gene expression using pooled RNA from liver of rats fed either a control purified amino acid diet (DL-methionine content of 0.86%) (CON) or a methionine-restricted diet (DL-methionine content of 0.172%)(MR). Rats were fed Purina rodent diet 5001 until 32 days of age and were then randomly assigned to be fed CON diet or MR diet for 20 months.

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The opposing impacts of dietary methionine restriction on tumor growth in immunodeficient and immunocompetent mice

Project description:Methionine, a sulfur-containing essential amino acid, is a key component of dietary proteins important for protein synthesis, sulfur metabolism, antioxidant defense, and signaling. However, the role of methionine in cancer progression remains inconclusive. On one hand, dietary methionine restriction is known to repress cancer growth and improve cancer therapy in xenografted tumors. On the other hand, methionine is also critical for T cell activation and differentiation, making it a potential tumor suppression nutrient by enhancing T cell-mediated anti-tumor immunity. Here we investigated the interaction between dietary methionine, immune cells, and cancer cells by allografting CT26.WT mouse colon carcinoma cells into immunocompetent Balb/c mice or immunodeficient NSG mice, then analyzed how dietary methionine contents affect their growth. Our results show that dietary methionine restriction suppresses tumor growth in immunodeficient NSG mice but promotes tumor progression in immunocompetentt Balb/c mice.

2023-06-14 | GSE165993 | GEO

Genome-wide transcriptome analysis of chickens during dietary methionine restriction reveals compromised immune competency

Project description:The goal of this study was to compare next-generation sequencing (NGS)-derived liver and pectoralis major transcriptome profilings (RNA-seq) of chicken fed control diet to treatment birds fed methionine restriction diet. We sequenced mRNA from 10 Gallus gallus males fed either control (L-Methionine) or L-Methionine-deficient diet (5 control and 5 treatment) from 3-5 weeks of age. We sequenced both liver and the pectoralis major muscle.

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Impact of dietary methionine, tryptophan, and niacin deficiency on gut microbiota in mice.

Project description:Emerging evidence indicates that selective nutrient restriction can reproduce metabolic benefits. Although methionine and branched-chain amino acid limitation improve metabolism and reshape the gut microbiome, the effects of other nutrients are still unclear. In this study, we examine the consequences of restricting methionine, tryptophan, and niacin, and find that their transient deprivation induces significant changes in gut microbiota.

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Effects of 20 months Dietary Methionine Restriction on Gene Expression in inguinal white adipose tissue of Fischer 344 Rats

Project description:Dietary methionine restriction (MR) has been shown to increase lifespan and decrease adiposity in rodents. This study was designed to examine the transcriptional effects of MR in metabolically relevant tissues. This experiment contains data from the inguinal white adipose tissue (IWAT). We analyzed MR-induced changes in gene expression using pooled RNA from IWAT of rats fed either a control purified amino acid diet (DL-methionine content of 0.86%) (CON) or a methionine-restricted diet (DL-methionine content of 0.172%)(MR). Rats were fed Purina rodent diet 5001 until 32 days of age and were then randomly assigned to be fed CON diet or MR diet for 20 months.

2013-07-01 | E-GEOD-28599 | biostudies-arrayexpress

Methionine availability influences essential H3K36me3 dynamics during cell differentiation

Project description:Methionine availability influences essential H3K36me3 dynamics during cell differentiation

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