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NAD(P)H:quinone oxidoreductase 1-compromised human bone marrow endothelial cells exhibit decreased adhesion molecule expression and CD34+ hematopoietic cell adhesion. 2010

Hongfei Zhou, and Donna Dehn, and Jadwiga K Kepa, and David Siegel, and Devon E Scott, and Wei Tan, and David Ross
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.

NAD(P)H:quinone oxidoreductase 1 (NQO1) deficiency resulting from a homozygous NQO1*2 polymorphism has been associated with an increased risk of benzene-induced myeloid toxicity and a variety of de novo and therapy-induced leukemias. Endothelial cells in human bone marrow form one of the two known hematopoietic stem cell microenvironments and are one of the major cell types that express NQO1 in bone marrow. We have used a transformed human bone marrow endothelial cell (TrHBMEC) line to study the potential impact of a lack of NQO1 activity on adhesion molecule [endothelial leukocyte adhesion molecule 1 (E-selectin), vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1] expression and functional adhesion to bone marrow progenitor cells. We used both 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1, and anti-NQO1 small interfering RNA to abrogate NQO1 activity. Real-time reverse transcription-polymerase chain reaction data demonstrated a significant inhibition of tumor necrosis factor (TNF)alpha-induced E-selectin mRNA levels after ES936 pretreatment. Immunoblot assays demonstrated a significant reduction in TNFalpha-stimulated E-selectin, VCAM-1, and ICAM-1 proteins after inhibition or knockdown of NQO1. The mechanisms underlying this effect remain undefined, but modulation of nuclear factor-kappaB (p65), c-Jun, and activating transcription factor 2, transcriptional regulators of adhesion molecules, were observed after inhibition or knockdown of NQO1. Decreased level of E-selectin, VCAM-1, and ICAM-1 also resulted in a functional deficit in adhesion. A parallel plate flow chamber study demonstrated a marked reduction in CD34(+) cell (KG1a) adhesion to NQO1-deficient TrHBMECs relative to controls. The reduced adhesive ability of TrHBMECs may affect the function of the vascular stem cell niche and also may contribute to the increased susceptibility of polymorphic individuals lacking NQO1 to leukemias and hematotoxicants such as benzene.

UI MeSH Term Description Entries
D001854 Bone Marrow Cells Cells contained in the bone marrow including fat cells (see ADIPOCYTES); STROMAL CELLS; MEGAKARYOCYTES; and the immediate precursors of most blood cells. Bone Marrow Cell,Cell, Bone Marrow,Cells, Bone Marrow,Marrow Cell, Bone,Marrow Cells, Bone
D002448 Cell Adhesion Adherence of cells to surfaces or to other cells. Adhesion, Cell,Adhesions, Cell,Cell Adhesions
D002461 Cell Line, Transformed Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals. Transformed Cell Line,Cell Lines, Transformed,Transformed Cell Lines
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006412 Hematopoietic Stem Cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Colony-Forming Units, Hematopoietic,Progenitor Cells, Hematopoietic,Stem Cells, Hematopoietic,Hematopoietic Progenitor Cells,Cell, Hematopoietic Progenitor,Cell, Hematopoietic Stem,Cells, Hematopoietic Progenitor,Cells, Hematopoietic Stem,Colony Forming Units, Hematopoietic,Colony-Forming Unit, Hematopoietic,Hematopoietic Colony-Forming Unit,Hematopoietic Colony-Forming Units,Hematopoietic Progenitor Cell,Hematopoietic Stem Cell,Progenitor Cell, Hematopoietic,Stem Cell, Hematopoietic,Unit, Hematopoietic Colony-Forming,Units, Hematopoietic Colony-Forming
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014409 Tumor Necrosis Factor-alpha Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS. Cachectin,TNF-alpha,Tumor Necrosis Factor Ligand Superfamily Member 2,Cachectin-Tumor Necrosis Factor,TNF Superfamily, Member 2,TNFalpha,Tumor Necrosis Factor,Cachectin Tumor Necrosis Factor,Tumor Necrosis Factor alpha
D015151 Immunoblotting Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies. Dot Immunoblotting,Electroimmunoblotting,Immunoelectroblotting,Reverse Immunoblotting,Immunoblotting, Dot,Immunoblotting, Reverse,Dot Immunoblottings,Electroimmunoblottings,Immunoblottings,Immunoblottings, Dot,Immunoblottings, Reverse,Immunoelectroblottings,Reverse Immunoblottings
D015815 Cell Adhesion Molecules Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. Cell Adhesion Molecule,Intercellular Adhesion Molecule,Intercellular Adhesion Molecules,Leukocyte Adhesion Molecule,Leukocyte Adhesion Molecules,Saccharide-Mediated Cell Adhesion Molecules,Saccharide Mediated Cell Adhesion Molecules,Adhesion Molecule, Cell,Adhesion Molecule, Intercellular,Adhesion Molecule, Leukocyte,Adhesion Molecules, Cell,Adhesion Molecules, Intercellular,Adhesion Molecules, Leukocyte,Molecule, Cell Adhesion,Molecule, Intercellular Adhesion,Molecule, Leukocyte Adhesion,Molecules, Cell Adhesion,Molecules, Intercellular Adhesion,Molecules, Leukocyte Adhesion
D016660 NAD(P)H Dehydrogenase (Quinone) A flavoprotein that reversibly catalyzes the oxidation of NADH or NADPH by various quinones and oxidation-reduction dyes. The enzyme is inhibited by dicoumarol, capsaicin, and caffeine. DT Diaphorase,Menadione Reductase,Phylloquinone Reductase,Quinone Reductase,Vitamin K Reductase,Diaphorase, DT,Reductase, Menadione,Reductase, Phylloquinone,Reductase, Quinone,Reductase, Vitamin K

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