Methionine Dependence of Cancer

Kaiser, Peter

doi:10.3390/biom10040568

Cited by 115 publications

(118 citation statements)

References 78 publications

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“…This was confirmed by Judde et al when it was demonstrated that overall transmethylation was strongly reduced in methionine-independent revertants derived from the methionine-addicted cancer cells (12, 13). The phenomenon of methionine-addicted cancer cells was later termed the Hoffman-effect (9).…”

Section: Discussionmentioning

confidence: 99%

The linkage of methionine addiction, overmethylation of histone H3 lysines and malignancy demonstrated when cancer cells revert to methionine-independence

Yamamoto

Inubushi²,

Han

et al. 2020

Preprint

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Methionine addiction is a fundamental and general hallmark of cancer. Methionine addiction results from the overuse of methionine by cancer cells for excess transmethylation reactions. In order to identify excess transmethylation reactions in cancer, we compared the histone H3 lysine methylation status between methionine-addicted cancer cells, normal cells and revertants of methionine-addicted cancer cells which regained methionine independence and lost malignancy. The levels of H3K4me3, H3K9me3 and pan-methyl lysine of histone H3 were elevated in methionine-addicted cancer cells in vitro compared to methionine-independent revertants isolated from the cancer cells and to normal cells. Tumorigenicity in nude mice was highly reduced in the methionine-independent revertants compared to the parental cells. The methionine-independent revertants no longer overmethylated pan-methyl lysine of H3, H3K4me3 and H3K9me3. Our previous studies showed that methionine restriction (MR) selectively arrests methionine-addicted cancer cells due to loss of histone H3 lysine methylation, which was stable in normal cells under MR. Our previous and present results suggest that overmethylation of histone H3 lysine is necessary for methionine addiction of cancer, required for the growth of cancer cells in vitro and in vivo, and necessary for malignancy. Methionine addiction has revealed fundamental molecular changes necessary for malignancy and presents great potential as a pan-cancer therapeutic target.Signiificance StatementAll cancer cell types are methionine-addicted. Methionine addiction is due to the overuse of methionine by cancer cells for excess transmethylation reactions. In the present study, we showed that the level of histone H3 lysine methylation was elevated in methionine-addicted cancer cells compared to normal fibroblasts and methionine-independent revertants with reduced malignancy that were derived from the methionine-addicted cancer cells. These results suggest that overmethylation of histone H3 lysine is necessary for methionine addiction of cancer and malignancy itself. Methionine addiction has revealed fundamental molecular changes necessary for malignancy and has been shown to be a universal therapeutic target in numerous pre-clinical studies of all major cancer types and has great clinical potential.

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Section: Discussionmentioning

confidence: 99%

The linkage of methionine addiction, overmethylation of histone H3 lysines and malignancy demonstrated when cancer cells revert to methionine-independence

Yamamoto

Inubushi²,

Han

et al. 2020

Preprint

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“…This arrest can be induced in mammalian and yeast cells by SAM limitation or methionine depletion. Cells show robust arrest in the G1 phase of the cell cycle due to the lack of stable pre-replication (pre-RC) complexes to initiate the S phase and a delay in G2/M is also observed [ 29 ]. The metabolic profiles resulting from DT8-treated cell lysates showed methionine depletion, which could, at least in part, explain the effect of the new biphenyl nicotinamide derivative DT8 ( 3 ) on cell cycle where it induced a blockade in the G1 phase at low doses and a delay in the G2/M phases.…”

Section: Discussionmentioning

confidence: 99%

“…The large overlap in the MCF-7 metabolic profiles of DT-8 and VIN, when compared with K, would suggest a similar mechanism of action but, as above observed, it is likely that DT-8 acts preferentially with respect to VIN, by mechanisms related to methionine depletion or S -adenosylmethionine (SAM) limitation, which, on the other hand, should be well associated with the cell cycle alterations observed with the DT-8 through a block in phase G1 at low doses [ 8 ]. The role in the control of the cell cycle of methionine depletion and/or SAM limitation may be linked to the control of the pre-replication complex (pre-RC) associated with the cell division cycle 6 (Cdc6) protein [ 29 ]. The formation of the pre-RC complex during the G1 phase is essential for chromosome replication to occur only once per cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine

et al. 2020

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A 1H-NMR-based metabolomic study was performed on MCF-7 cell lines treated with a novel nicotinamide derivative (DT-8) in comparison with two drugs characterized by a well-established mechanism of action, namely the DNA-metalating drug cisplatin (cis-diamminedichloridoplatinum(II), CDDP) and the antimitotic drug vinblastine (vinblastine, VIN). The effects of the three compounds, each one at the concentration corresponding to the IC50 value, were investigated, with respect to the controls (K), by the 1H-NMR of cells lysates and multivariate analysis (MVA) of the spectroscopic data. Relevant differences were found in the metabolic profiles of the different treatments with respect to the controls. A large overlap of the metabolic profiles in DT-8 vs. K and VIN vs. K suggests a similar biological response and mechanism of action, significantly diverse with respect to CDDP. On the other hand, DT8 seems to act by disorganizing the mitotic spindle and ultimately blocking the cell division, through a mechanism implying methionine depletion and/or S-adenosylmethionine (SAM) limitation.

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“…Cancer cells show a higher demand for nutritional supplies and certain metabolites compared to normal cells [ 4 , 74 ]. As mentioned above, the methionine metabolism is tightly regulated and coupled to other metabolic cycles ( Figure 1 ).…”

Section: Methionine and Its Role In Cancermentioning

confidence: 99%

Sensing and Signaling of Methionine Metabolism

Lauinger

Kaiser

2021

Metabolites

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Availability of the amino acid methionine shows remarkable effects on the physiology of individual cells and whole organisms. For example, most cancer cells, but not normal cells, are hyper dependent on high flux through metabolic pathways connected to methionine, and diets restricted for methionine increase healthy lifespan in model organisms. Methionine’s impact on physiology goes beyond its role in initiation of translation and incorporation in proteins. Many of its metabolites have a major influence on cellular functions including epigenetic regulation, maintenance of redox balance, polyamine synthesis, and phospholipid homeostasis. As a central component of such essential pathways, cells require mechanisms to sense methionine availability. When methionine levels are low, cellular response programs induce transcriptional and signaling states to remodel metabolic programs and maintain methionine metabolism. In addition, an evolutionary conserved cell cycle arrest is induced to ensure cellular and genomic integrity during methionine starvation conditions. Methionine and its metabolites are critical for cell growth, proliferation, and development in all organisms. However, mechanisms of methionine perception are diverse. Here we review current knowledge about mechanisms of methionine sensing in yeast and mammalian cells, and will discuss the impact of methionine imbalance on cancer and aging.

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Methionine Dependence of Cancer

Cited by 115 publications

References 78 publications

The linkage of methionine addiction, overmethylation of histone H3 lysines and malignancy demonstrated when cancer cells revert to methionine-independence

The linkage of methionine addiction, overmethylation of histone H3 lysines and malignancy demonstrated when cancer cells revert to methionine-independence

Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine

Sensing and Signaling of Methionine Metabolism

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