The opposing impacts of dietary methionine restriction on tumor growth in immunodeficient and immunocompetent mice
Ontology highlight
ABSTRACT: 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.
Project description:Since both endogenous synthesis in tumor cells and bacterial sulfur reduction activities are sources of H2S in colon cancer microenvironment, in addition to using CBS -/+ mice, we also investigated the roles of reducing H2S through adopting a sulfur amino acid restriction diet (SARD) (0.15% methionine and 0% cystine) on immunotherapy (anti-PD-L1) of colon cancer. Tumor bulk sequencing was performed in cecum orthotopic CT26 tumors collected from IgG and anti-PD-L1 treated mice both receiving normal diet and SARD.
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.
Project description:Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent versus methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generic rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, the methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but trigger different outcomesin methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and tight junctions in the cellular response to methionine stress in melanoma.
Project description:Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent versus methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generic rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, the methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but trigger different outcomesin methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and tight junctions in the cellular response to methionine stress in melanoma.
2023-05-03 | GSE225944 | GEO
Project description:Dietary methionine restriction impairs anti-tumor immunity in part through gut microbiota
Project description:Intestinal cancers are highly responsive to their nutrient environment. However, previous studies integrating nutrition into the network of cancer progression are largely inconsistent. We therefore investigated the effects of dietary restriction, which is the most consistently found beneficial nutritional intervention, on the development of intestinal stem cell tumors in a Drosophila melanogaster model. Submission to dietary restriction led to a decline in tumor mass and a morphological as well as functional rehabilitation of the intestine. Nevertheless, flies submitted to dietary restriction exhibited a drastically reduced lifespan due to substantial loss of body mass. To circumvent these destructive consequences, we applied a nutritional regimen consisting of alternating phases of dietary restriction and a fully nutritious diet. Strikingly, the recurrent diet reduced tumor mass and reinstated gut functionality to the same extend as continuous dietary restriction, while restoring the lifespan of tumor-bearing flies back to the level of healthy controls.
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.
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.