Homocysteine Increases Methionine Synthase mRNA Level in Caco-2 Cells

Ortiou, Sandrine; Alberto, Jean-Marc; Guéant, Jean‐Louis; Merten, Marc

doi:10.1159/000080350

Cited by 11 publications

(8 citation statements)

References 23 publications

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“…As a consequence, it can be concluded that vinblastine sensitivity is a direct consequence of mdr-1 expression in HepG2 cells. A 100 nM cobalamin concentration led to a dramatic increase in MS activity as already shown in cancer intestinal cells [38] and also in about a two log lower GI 50 of vinblastine (Figures 4 and 5). However, the GI 50 of cobalamin (100 nM) ranged above the physiological plasma concentration (0.1 to 1 nM).…”

Section: Discussionsupporting

confidence: 73%

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Marguerite¹,

Béri-Dexheimer²,

Ortiou³

et al. 2007

Cell Physiol Biochem

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Background: P-glycoprotein (Pgp), produced by multidrug resistance-1 gene (mdr-1), is a main mechanism developed by cancer cells to guard against anti-cancer drugs. Alterations of DNA methylation of the mdr-1 gene promoter are known to be linked to mdr-1 gene expression and are probably related to intracellular S-adenosyl-methionine. We here used HepG2 cells to determine the role of the methionine cycle (through the use of the Methionine-Synthase (MS) cofactor, cobalamin) on mdr-1 gene expression. Methods: Semiquantitative RT-PCR of mdr-1 gene, cellular retention of rhodamine-123, and vinblastine cytotoxicity were carried out on cells cultivated with and without cobalamin. Methylation status of the mdr-1 gene promoter was determined by methylation-specific PCR. Results: Addition of cobalamin to the cells led to an increase in MS activity, to a significant decrease in mdr-1 gene expression which is correlated to an increase in retention of the Pgp substrate Rhodamine 123. Furthermore, cobalamin potentiated cell sensitivity to vinblastine to the same range as that of the Pgp blocker verapamil and prevented methotrexate-induced up-regulation of mdr-1 gene expression. However, no modification in methylation of the mdr-1 gene promoter was observed. Conclusion: Cobalamin downregulates mdr-1 gene expression, as well as Pgp expression and function, and significantly increases cytotoxicity of vinblastine. The identification of this novel way of diminishing cellular resistance to the chemotherapeutic agent vinblastine holds promises of leading to better treatments for cancer patients.

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Section: Discussionsupporting

confidence: 73%

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Marguerite¹,

Béri-Dexheimer²,

Ortiou³

et al. 2007

Cell Physiol Biochem

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“…Translation of methionine synthase, the enzyme that functions immediately downstream of MTHFR, by transferring the methyl group from 5-methyltetrahydrofolate to homocysteine for the synthesis of methionine, is influenced by a functional internal ribosome entry site element (43). It has also previously been reported that methionine synthase mRNA levels are increased by treatment of cultured cells with Hcy (44).…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Increases the Expression of Methylenetetrahydrofolate Reductase through the IRE1 Transducer

Leclerc

Rozen

2008

Journal of Biological Chemistry

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Methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate and homocysteine metabolism, influences many cellular processes including methionine and nucleotide synthesis, methylation reactions, and maintenance of homocysteine at nontoxic levels. Mild deficiency of MTHFR is common in many populations and modifies risk for several complex traits including vascular disease, birth defects, and cancer. We recently demonstrated that MTHFR can be up-regulated by NF-B, an important mediator of cell survival that is activated by endoplasmic reticulum (ER) stress. This observation, coupled with the reports that homocysteine can induce ER stress, prompted us to examine the possible regulation of MTHFR by ER stress. We found that several well characterized stress inducers (tunicamycin, thapsigargin, and A23187) as well as homocysteine could increase Mthfr mRNA and protein in Neuro-2a cells. The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression, whereas a reported inhibitor of c-Jun (SP600125) and a dominant-negative derivative of c-Jun N-terminal kinase-1 reduced MTHFR activation. We conclude that ER stress increases MTHFR expression and that IRE1 and c-Jun mediate this activation. These findings provide a novel mechanism by which the ER can regulate homeostasis and allude to an important role for MTHFR in cell survival.

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“…Cysteine dioxygenase activity is increased in response to increasing levels of dietary methionine at post-transnlational levels due to suppression of degradation of the enzyme via polyubiquitination [7,8]. Methionine synthase levels are increased by homocysteine at the transcriptional level [9]. On the other hand, the activation of glutamate-cysteine ligase in glutathione synthesis is decreased in response to increased levels of dietary protein or methionine [10].…”

Section: The Mercaptopyruvate Pathway and Mercaptopyruvate Sulfurtranmentioning

confidence: 99%

The Mercaptopyruvate Pathway in Cysteine Catabolism: A Physiologic Role and Related Disease of the Multifunctional 3-Mercaptopyruvate Sulfurtransferase

Nagahara

Sawada²

2006

CMC

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The conversion of cysteine to 3-sulfino-alanine is a major pathway in cysteine catabolism. Cysteine dioxygenase catalyzes the reaction and dietary intake of the essential amino acid methionine and the semi-essential amino acid cysteine increases the level of this enzyme by suppressing enzyme degradation via polyubiquitination. The production of cellular antioxidants such as glutathione, thioredoxin, and their families is important in cysteine metabolism, and these cellular antioxidants have critical roles in the maintenance of the cellular redox status. The mercaptopyruvate pathway, in which cysteine or aspartate transaminase catalyzes the transamination from cysteine to 3-mercaptopyruvate and then 3-mercaptopyruvate sulfurtransferase catalyzes the transsulfuration from 3-mercaptopyruvate to pyruvate, also contributes to maintain the cellular redox. 3-Mercaptopyruvate sulfurtransferase serves as an antioxidant protein: when the enzyme is exposed to stoichiometric amounts of the oxidant hydrogen peroxide, it is inhibited via the formation of low redox sulfenate at the catalytic site cysteine. On the other hand, activity is restored by the reductant dithiothreitol or reduced thioredoxin. 3-Mercaptopyruvate sulfurtransferase also detoxifies cyanide via transsulfuration from a stable persulfide at the catalytic site cysteine, a reaction intermediate, suggesting that cyanide detoxification is not necessarily an enzymatic reaction. Furthermore, a congenital defect of the enzyme causes mercaptolactate-cysteine disulfiduria associated with or without mental retardation, although the pathogenesis remains unclear. These facts suggest that 3-mercaptopyruvate sulfurtransferase has physiologic roles as an antioxidant and a cyanide antidote; is essential for neural function, and participates in cysteine degradation.

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Homocysteine Increases Methionine Synthase mRNA Level in Caco-2 Cells

Cited by 11 publications

References 23 publications

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Endoplasmic Reticulum Stress Increases the Expression of Methylenetetrahydrofolate Reductase through the IRE1 Transducer

The Mercaptopyruvate Pathway in Cysteine Catabolism: A Physiologic Role and Related Disease of the Multifunctional 3-Mercaptopyruvate Sulfurtransferase

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