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Article ; Online: Rescue of Methionine Dependence by Cobalamin in a Human Colorectal Cancer Cell Line.

Garg, Sarita / Miousse, Isabelle R

2024 Volume 16, Issue 7

Abstract: Methionine dependence is a characteristic of most cancer cells where they are unable to proliferate when the essential amino acid methionine is replaced with its precursor homocysteine in the growing media. Normal cells, on the other hand, thrive under ... ...

Abstract	Methionine dependence is a characteristic of most cancer cells where they are unable to proliferate when the essential amino acid methionine is replaced with its precursor homocysteine in the growing media. Normal cells, on the other hand, thrive under these conditions and are referred to as methionine-independent. The reaction that adds a methyl group from 5-methyltetrahydrofolate to homocysteine to regenerate methionine is catalyzed by the enzyme methionine synthase with the cofactor cobalamin (vitamin B
MeSH term(s)	Humans ; Methionine/pharmacology ; 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase ; Vitamin B 12/pharmacology ; Homocystine ; Racemethionine ; Cell Line ; Homocysteine ; Colorectal Neoplasms/drug therapy
Chemical Substances	Methionine (AE28F7PNPL) ; 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase (EC 2.1.1.13) ; Vitamin B 12 (P6YC3EG204) ; Homocystine (462-10-2) ; Racemethionine (73JWT2K6T3) ; Homocysteine (0LVT1QZ0BA)
Language	English
Publishing date	2024-03-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu16070997
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Article: Increased response to immune checkpoint inhibitors with dietary methionine restriction.

Morehead, Lauren C / Garg, Sarita / Wallis, Katherine F / Siegel, Eric R / Tackett, Alan J / Miousse, Isabelle R

bioRxiv : the preprint server for biology

2023

Abstract: Dietary methionine restriction, defined as reduction of methionine intake by around 80%, reproducibly decreases tumor growth and synergizes with cancer therapies. Here, we combined dietary methionine restriction with immune checkpoint inhibitors in a ... ...

Abstract	Dietary methionine restriction, defined as reduction of methionine intake by around 80%, reproducibly decreases tumor growth and synergizes with cancer therapies. Here, we combined dietary methionine restriction with immune checkpoint inhibitors in a model of colon adenocarcinoma.
Language	English
Publishing date	2023-04-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.05.535695
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Article ; Online: 4006 Methionine Dependence in Cancer

Isabelle Miousse

Journal of Clinical and Translational Science, Vol 4, Pp 12-

From Metabolic Phenotype to Therapy

2020 Volume 12

Abstract: OBJECTIVES/GOALS: Methionine dependence was described 45 years ago as an increased reliance on an exogenous supply of the essential amino acid methionine in most cancer cells compared to normal cells. Methionine depletion, using either synthetic diets or ...

Abstract	OBJECTIVES/GOALS: Methionine dependence was described 45 years ago as an increased reliance on an exogenous supply of the essential amino acid methionine in most cancer cells compared to normal cells. Methionine depletion, using either synthetic diets or the enzyme methioninase, potentiates the effects of chemotherapy and radiotherapy in tumor-bearing animal models. Two main obstacles prevent methionine dependence from integrating the clinical treatment of cancer. The first is the weight loss associated with methionine depletion therapy, increasing the risk of cachexia in patients. The second is the stubborn absence of a mechanism to explain the inability of cancer cells to adapt to low methionine levels. METHODS/STUDY POPULATION: To address these two obstacles, we are using an immunocompetent murine model of metastatic melanoma to compare the effects of complete methionine deprivation with a moderate, 75-80% methionine restriction similar to the one used to increase lifespan in animal models. In an effort to identify a mechanism of action, we also performed a proteomic screen of two melanoma cell lines divergent for methionine dependence under methionine stress. RESULTS/ANTICIPATED RESULTS: We recently showed that methionine restriction is sufficient to provide gains in treating local and metastatic lesions in vivo, without weight loss. We observed few differences in pathway activation between the two cell lines in response to methionine stress, despite proliferation being cut by half in the methionine dependent cell line. We expect that subcellular translocation events may provide further information on the molecular bases of methionine dependence. DISCUSSION/SIGNIFICANCE OF IMPACT: A moderate restriction in methionine is sufficient to recapitulate the benefits of methionine depletion in cancer, without weight loss. The mechanism behind this effect remains unknown. This work contributes towards the integration of methionine dependence into clinical practice and the discovery of novel drug targets.
Keywords	Medicine ; R
Subject code	610
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	Cambridge University Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sex-Specific Effects of Dietary Methionine Restriction on the Intestinal Microbiome.

Wallis, Katherine F / Melnyk, Stepan B / Miousse, Isabelle R

Nutrients

2020 Volume 12, Issue 3

Abstract: Dietary methionine restriction is associated with improved health outcomes and an increase in lifespan in animal models. We have previously shown that an increase in dietary methionine induces alteration in the intestinal microbiome. The composition of ... ...

Abstract	Dietary methionine restriction is associated with improved health outcomes and an increase in lifespan in animal models. We have previously shown that an increase in dietary methionine induces alteration in the intestinal microbiome. The composition of the intestinal microbiota is a determinant of health and we, therefore, hypothesized that dietary methionine restriction would also induce changes in the murine microbiome. After one month on a methionine-restricted diet, five-month-old male and female C57BL/6 mice had decreased levels of serum methionine, without changes in body weight. We identified a decrease in the hepatic methylation status of animals fed a methionine-restricted diet compared to controls. This decrease was not associated with changes in DNA or protein methylation in the liver. In males, we saw an increase in families
MeSH term(s)	Animals ; Bacteria/classification ; Bacteria/growth & development ; Female ; Gastrointestinal Microbiome ; Male ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Sex Characteristics
Chemical Substances	Methionine (AE28F7PNPL)
Language	English
Publishing date	2020-03-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu12030781
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Article ; Online: 32219 Differences in cell death in methionine versus cysteine depletion

Katherine F. Wallis / Isabelle R. Miousse

Journal of Clinical and Translational Science, Vol 5, Pp 10-

2021 Volume 11

Abstract: ABSTRACT IMPACT: Reducing methionine levels has repeatedly been shown to reduce cancer growth in vivo, while at the same time increasing lifespan in healthy animals. However, the mechanisms behind the beneficial effects of methionine restriction are ... ...

Abstract	ABSTRACT IMPACT: Reducing methionine levels has repeatedly been shown to reduce cancer growth in vivo, while at the same time increasing lifespan in healthy animals. However, the mechanisms behind the beneficial effects of methionine restriction are currently unknown. OBJECTIVES/GOALS: We hypothesized that comparing the response of a cancer cell line to depletion of the amino acids methionine and cysteine would give us insight into the critical role of these two closely related amino acids in cancer, and help advance methionine restriction on the translational science spectrum. METHODS/STUDY POPULATION: We used the human melanoma cell line A101D to analyze the response to three conditions: methionine depletion, methionine replacement with homocysteine, and cysteine depletion in vitro. We measured proliferation/viability, gene expression patterns, and glutathione levels. We also assessed ferroptotic versus apoptotic cell death. We then used a normal human fibroblast cell line to compare responses. RESULTS/ANTICIPATED RESULTS: The transcription factors ATF4 and NRF2 were activated by all three tested conditions in melanoma cells. Glutathione levels were decreased by ˜40% in cells grown without methionine, and by 95% in cells grown without cysteine. Lipid peroxidation was increased in cells grown without cysteine, but not in cells grown without methionine. Inhibiting ferroptotic cell death partially rescued proliferation in cysteine-depleted but not in methionine-depleted cells. Almost 70% of cells grown in methionine-depleted media stained positive for Annexin V, an indicator of apoptosis, compared to only 20% of cells grown in cysteine-depleted media. In normal cells, ferrostatin recued proliferation/viability to 86% of control levels in cysteine-depleted cells. Ferrostatin did not affect methionine-depleted normal cells. DISCUSSION/SIGNIFICANCE OF FINDINGS: These results indicate that methionine depletion leads to apoptosis, while cysteine depletion leads to ferroptosis. We found overlapping pathways activated ...
Keywords	Medicine ; R
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Cambridge University Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Increased Response to Immune Checkpoint Inhibitors with Dietary Methionine Restriction in a Colorectal Cancer Model.

Morehead, Lauren C / Garg, Sarita / Wallis, Katherine F / Simoes, Camila C / Siegel, Eric R / Tackett, Alan J / Miousse, Isabelle R

Cancers

2023 Volume 15, Issue 18

Abstract: Dietary methionine restriction (MR), defined as a reduction of methionine intake by around 80%, has been shown to reproducibly decrease tumor growth and synergize with cancer therapies. In this study, we combined DMR with immune checkpoint inhibitors ( ... ...

Abstract	Dietary methionine restriction (MR), defined as a reduction of methionine intake by around 80%, has been shown to reproducibly decrease tumor growth and synergize with cancer therapies. In this study, we combined DMR with immune checkpoint inhibitors (ICIs) in a model of colon adenocarcinoma. In vitro, we observed that MR increased the expression of MHC-I and PD-L1 in both mouse and human colorectal cancer cells. We also saw an increase in the gene expression of STING, a known inducer of type I interferon signaling. Inhibition of the cGAS-STING pathway, pharmacologically or with siRNA, blunted the increase in MHC-I and PD-L1 surface and gene expression following MR. This indicated that the cGAS-STING pathway, and interferon in general, played a role in the immune response to MR. We then combined dietary MR with ICIs targeting CTLA-4 and PD-1 in an MC38 colorectal cancer tumor model developed in immunocompetent C57BL/6 mice. The combination treatment was five times more effective at reducing the tumor size than ICIs alone in male mice. We noted sex differences in the response to dietary MR, with males showing a greater response than females. Finally, we observed an increase in membrane staining for the PD-L1 protein in MC38 tumors from animals who were fed an MR diet. MHC-I was highly expressed in all tumors and showed no expression difference when comparing tumors from control and MR-treated mice. These results indicated that MR increased PD-L1 expression both in vitro and in vivo and improved the response to ICIs in mice.
Language	English
Publishing date	2023-09-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15184467
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Article ; Online: Resveratrol induces major histocompatibility complex class I antigen presentation in a STING-dependent and independent manner in melanoma.

Morehead, Lauren C / Koss, Brian / Fil, Daniel / Heflin, Billie / Garg, Sarita / Wallis, Katherine F / Tackett, Alan J / Miousse, Isabelle R

Molecular immunology

2023 Volume 163, Page(s) 188–195

Abstract: Immune checkpoint inhibitor therapy has drastically improved outcomes in treating cancer, particularly in melanoma. However, half of melanoma patients are resistant to treatment. One mechanism used by tumor cells to evade immune attack is to down- ... ...

Abstract	Immune checkpoint inhibitor therapy has drastically improved outcomes in treating cancer, particularly in melanoma. However, half of melanoma patients are resistant to treatment. One mechanism used by tumor cells to evade immune attack is to down-regulate major histocompatibility complex (MHC) class I molecules, which are required for cytotoxic CD8 T-cells to eliminate cancer cells. To increase immunotherapeutic efficacy, it is critical to identify how to restore MHC-I expression on cancer cells so that tumor antigens are presented. We found that resveratrol elevated MHC-I expression, so that tumor antigens are presented to cytotoxic CD8 T-cell killing. Through proteomic interrogation, we identified the STING pathway as a potential mechanism of action. Further studies indicated that resveratrol-mediated regulation of STING induced MHC-I expression potentially through both interferon-independent and dependent pathways. Our results have indicated the potential of STING to induce MHC-I expression independent of interferon signaling, broadening the potential of STING modulation as a tool to improve immune checkpoint blockade.
MeSH term(s)	Humans ; Antigen Presentation ; Antigens, Neoplasm ; Histocompatibility Antigens Class I ; HLA Antigens ; Interferons ; Major Histocompatibility Complex ; Melanoma/drug therapy ; Melanoma/pathology ; Proteomics ; Resveratrol/pharmacology
Chemical Substances	Antigens, Neoplasm ; Histocompatibility Antigens Class I ; HLA Antigens ; Interferons (9008-11-1) ; Resveratrol (Q369O8926L)
Language	English
Publishing date	2023-10-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2023.10.003
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Article ; Online: Characterization of methionine dependence in melanoma cells.

Garg, Sarita / Morehead, Lauren C / Bird, Jordan T / Graw, Stefan / Gies, Allen / Storey, Aaron J / Tackett, Alan J / Edmondson, Rick D / Mackintosh, Samuel G / Byrum, Stephanie D / Miousse, Isabelle R

Molecular omics

2024 Volume 20, Issue 1, Page(s) 37–47

Abstract: 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 ... ...

Abstract	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. We do know 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 its precursor homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent and methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generalized 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, methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of
MeSH term(s)	Animals ; Methionine/metabolism ; Melanoma/genetics ; Proteome ; S-Adenosylmethionine/metabolism ; Racemethionine ; Homocysteine
Chemical Substances	Methionine (AE28F7PNPL) ; Proteome ; S-Adenosylmethionine (7LP2MPO46S) ; Racemethionine (73JWT2K6T3) ; Homocysteine (0LVT1QZ0BA)
Language	English
Publishing date	2024-01-15
Publishing country	England
Document type	Journal Article
ISSN	2515-4184
ISSN (online)	2515-4184
DOI	10.1039/d3mo00087g
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Article ; Online: Differences in cell death in methionine versus cysteine depletion.

Wallis, Katherine F / Morehead, Lauren C / Bird, Jordan T / Byrum, Stephanie D / Miousse, Isabelle R

Environmental and molecular mutagenesis

2021 Volume 62, Issue 3, Page(s) 216–226

Abstract: Restriction of the sulfur amino acids methionine and cysteine has recently been proposed as potential adjuvant therapy in cancer. While cysteine depletion has been associated with ferroptotic cell death, methionine depletion has not. We hypothesized that ...

Abstract	Restriction of the sulfur amino acids methionine and cysteine has recently been proposed as potential adjuvant therapy in cancer. While cysteine depletion has been associated with ferroptotic cell death, methionine depletion has not. We hypothesized that comparing the response of melanoma cell lines to depletion of the amino acids methionine and cysteine would give us insight into the critical role in cancer of these two closely related amino acids. We analyzed the response to three conditions: methionine depletion, methionine replacement with homocysteine, and cysteine depletion. In cancer cells, the transcription factor ATF4 was induced by all three tested conditions. The replacement of methionine with homocysteine produced a strong ferroptotic gene signature. We also detected an activation of the NRF2 antioxidant pathway by both methionine and cysteine depletion. Total glutathione levels were decreased by 42% in melanoma cells grown without methionine, and by 95% in cells grown without cysteine. Lipid peroxidation was increased in cells grown without cysteine, but not in cells grown without methionine. Despite the large degree of overlap in gene expression between methionine and cysteine depletion, methionine depletion and replacement of methionine with homocysteine was associated with apoptosis while cysteine depletion was associated with ferroptosis. Glutamine depletion produced comparable gene expression patterns and was associated with a 28% decrease in glutathione. Apoptosis was detected in these cells. In this experiment, a strong ATF4-driven ferroptotic gene signature was insufficient to induce ferroptosis without a concomitant profound decrease in glutathione levels.
MeSH term(s)	Activating Transcription Factor 4/genetics ; Apoptosis/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; Chemotherapy, Adjuvant ; Cysteine/antagonists & inhibitors ; Cysteine/genetics ; Ferroptosis/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Homocysteine/genetics ; Humans ; Lipid Peroxidation/genetics ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/metabolism ; Methionine/antagonists & inhibitors ; Methionine/genetics ; NF-E2-Related Factor 2/genetics ; Transcriptome/genetics
Chemical Substances	ATF4 protein, human ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; Homocysteine (0LVT1QZ0BA) ; Activating Transcription Factor 4 (145891-90-3) ; Methionine (AE28F7PNPL) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2021-03-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	639145-x
ISSN	1098-2280 ; 0893-6692
ISSN (online)	1098-2280
ISSN	0893-6692
DOI	10.1002/em.22428
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Zs.B 2404: Show issues

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Article ; Online: Methylsulfonylmethane Serves as a Donor of Methyl Groups for Methylation of DNA in Human Liver HepaRG Cells.

Clement, Kirsten / McGill, Mitchell R / Miousse, Isabelle R / Young, Sean G / Melnyk, Stepan / Koturbash, Igor

Journal of dietary supplements

2022 Volume 20, Issue 6, Page(s) 950–962

Abstract: Methylsulfonylmethane (MSM), a natural organosulfur compound, is a popular dietary supplement sold both as a single product and as a constituent of multi-ingredient products. It has been postulated that MSM may serve as a donor for methyl groups for ... ...

Abstract	Methylsulfonylmethane (MSM), a natural organosulfur compound, is a popular dietary supplement sold both as a single product and as a constituent of multi-ingredient products. It has been postulated that MSM may serve as a donor for methyl groups for various cellular processes; however, studies have yet to demonstrate this. Therefore, the goal of this study was to determine whether or not MSM, supplemented to fully differentiated human HepaRG cells at physiologically-relevant concentrations, can serve as a donor for methyl groups for DNA methylation. For this purpose, methyl groups in the MSM molecule were labeled with deuterium (deuterated) and incorporation of the labeled 5-methylcytosine into the HepaRG cell DNA was evaluated using liquid chromatography/mass spectrometry (LC-MS/MS). We report that MSM supplementation resulted in significant incorporation of deuterated product into DNA in a time- and dose-dependent fashion. These changes were not associated with increased 5-methylcytosine content, did not result in changes of DNA methylation or re-distribution of DNA methylation patterns between the retrotransposons LINE-1 and HERV18, and were not associated with cytotoxicity. In conclusion, short-term supplementation with MSM
MeSH term(s)	Humans ; Methylation ; 5-Methylcytosine/metabolism ; Chromatography, Liquid ; Tandem Mass Spectrometry ; Liver/metabolism ; DNA
Chemical Substances	dimethyl sulfone (9H4PO4Z4FT) ; 5-Methylcytosine (6R795CQT4H) ; DNA (9007-49-2)
Language	English
Publishing date	2022-12-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2460305-3
ISSN	1939-022X ; 1939-0211
ISSN (online)	1939-022X
ISSN	1939-0211
DOI	10.1080/19390211.2022.2153957
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