title: Phospholipase D activation mediates cobalamin-induced downregulation of Multidrug Resistance-1 gene and increase in sensitivity to vinblastine in HepG2 cells.
abstract: Failure of cancer chemotherapy due to multidrug resistance is often associated with altered Multidrug Resistance-1 gene expression. Cobalamin is the cofactor of methionine synthase, a key enzyme of the methionine cycle which synthesizes methionine, the precursor of cell S-adenosyl-methionine synthesis. We previously showed that cobalamin was able to down-regulate Multidrug Resistance-1 gene expression. Herein we report that this effect occurs through cobalamin-activation of phospholipase D activity in HepG2 cells. Cobalamin-induced down-regulation of Multidrug Resistance-1 gene expression was similar to that induced by the phospholipase D activator oleic acid and was negatively modulated by the phospholipase D inhibitor n-butanol. Cobalamin increased cell S-adenosyl-methionine content, which is the substrate for phosphatidylethanolamine-methyltransferase-dependent phosphatidylcholine production. We showed that cobalamin-induced increase in cell phosphatidylcholine production was phosphatidylethanolamine-methyltransferase-dependent. Oleic acid-dependent activation of phospholipase D was accompanied by an increased sensitivity to vinblastine of HepG2 cells while n-butanol enhanced the resistance of the cells to vinblastine. These data indicate that cobalamin mediates down-regulation of Multidrug Resistance-1 gene expression through increased S-adenosyl-methionine and phosphatidylcholine productions and phospholipase D activation. This points out phospholipase D as a potential target to down-regulate Multidrug Resistance-1 gene expression for improving chemotherapy efficacy.
authors.affiliation: Laboratory of Nutrition, Genetics and Exposition to Environmental Risks, Faculty of Medicine, Vandoeuvre-lès-Nancy F-54505, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Marguerite
authors.forename: Effrosyni
authors.initials: E
authors.lastname: Gkikopoulou
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Alberto
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.forename: Marc
authors.initials: M
authors.lastname: Merten
mesh_terms: D020001:1-Butanol / Q000494:pharmacology; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001629:Bezafibrate / Q000494:pharmacology; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D019301:Oleic Acid / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000096:biosynthesis; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology*; D014805:Vitamin B 12 / Q000502:physiology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D020536:Enzyme Activators; D010713:Phosphatidylcholines; D019301:Oleic Acid; D014747:Vinblastine; D012436:S-Adenosylmethionine; D020001:1-Butanol; D050918:Phosphatidylethanolamine N-Methyltransferase; D010739:Phospholipase D; D014805:Vitamin B 12; D001629:Bezafibrate