title: Involvement of microRNA181a in differentiation and cell cycle arrest induced by a plant-derived antioxidant carnosic acid and vitamin D analog doxercalciferol in human leukemia cells.
abstract: 1,25-dihydroxyvitamin D3 (1,25D) has been shown to influence differentiation, cell proliferation and cell death in cultured leukemia cells. However, its clinical use is limited by its hypercalcemic effects. An analog of 1,25D, doxercalciferol (1-D2), has anti-tumor activity, with markedly reduced calcemic effects, which makes it a potential agent for clinical treatment of AML. Previous studies suggested that the combination of 1,25D with other agents, such as plant-derived antioxidants, can have additive or synergistic anti-cancer activities in leukemia cells. Here we report that 1-D2 induced monocytic differentiation of HL60 and U937 cells, and that the antioxidant carnosic acid (CA) enhanced 1-D2 induced differentiation and cell cycle arrest. MicroRNA181a (miR181a) expression was also reduced after exposure to CA/1-D2. Since the cell cycle regulator p27Kip1 has been shown to be a target of miR181a, we modulated miR181a levels to determine if it plays a role in CA/1-D2 induced differentiation and cell cycle arrest in AML cells. We found that transfection of antisense miR181a potentiated CA/1-D2-induced cell differentiation, while the transfection of precursor of miR181a partially inhibited the effect of CA/1-D2 on the differentiation. These findings imply that miR181a has a role in CA/1-D2- induced differentiation and cell cycle arrest of HL60 and U937 cells, and shows a broader participation of miR181a in cell cycle control in leukemia cells.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Duggal
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Harrison
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
authors.affiliation: Department of Pathology and Laboratory Medicine, UMD-New Jersey Medical School, 185 South Orange Ave, Newark, New Jersey, 07101-1709, USA.
authors.forename: Xuening
authors.initials: X
authors.lastname: Wang
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000975:Antioxidants / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004357:Drug Synergism; D004872:Ergocalciferols / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D010936:Plant Extracts / Q000494:pharmacology*; D020298:U937 Cells; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D045784:Abietanes; D000975:Antioxidants; D004872:Ergocalciferols; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D010936:Plant Extracts; D014815:Vitamins; C042533:1 alpha-hydroxyergocalciferol; C018381:salvin