Phospholipase D activation mediates cobalamin-induced downregulation of Multidrug Resistance-1 gene and increase in sensitivity to vinblastine in HepG2 cells

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• 作者：Vé ; ronique Marguerite¹ ; Effrosyni Gkikopoulou¹ ; Jean-Marc Alberto ; Jean-Louis Gué ; ant ; Marc Merten ; ^{Marc.Merten@univ-lorraine.fr}
• 关键词：ABC ; ATP-binding cassette ; Akt ; protein kinase B ; BCA ; bicinchoninic acid ; BCRP ; breast cancer resistance protein ; Bet ; betaine ; Beza ; bezafibrate ; BHMT ; betaine-homocysteine methyltransferase ; B-PC ; BODIPY-phosphatidylcholine ; B-LysoPBut ; BODIPY-lysophos
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2013
• 出版时间：February, 2013
• 年：2013
• 卷：45
• 期：2
• 页码：213-220
• 全文大小：762 K

文摘

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.