VEGF-induced ROS generation from NAD(P)H oxidases protects human leukemic cells from apoptosis.
Vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) play critical roles in vascular pathophysiology and in hematological malignancies. VEGF is supposed to utilize ROS as messenger intermediates downstream of the VEGF receptor-2. NAD(P)H oxidase (Nox) family is a major source of cellular ROS and is implicated in increased ROS production in tumor cells. We previously demonstrated that B1647 cells, a human leukemic cell line, express Nox2 and Nox4, both at mRNA and protein level. We suggest here that the VEGF-induced increase in ROS can be related to Nox2 and Nox4 activities. Nox-derived ROS are involved in early signaling events such as the autophosphorylation of VEGF receptor-2, and in the modulation of glucose uptake, a cellular activity strictly bound to VEGF-induced leukemic cell proliferation, as shown by experiments with antioxidants and Nox inhibitors and siRNA. Nox-generated ROS are required to sustain B1647 cell viability and proliferation; in fact, antioxidants such as EUK-134 or Nox inhibitors and siRNA direct cells to apoptotic cell death, suggesting that manipulation of cellular Nox2 and Nox4 could affect survival of leukemic cells.
Maraldi
Tullia
T
Department of Anatomy and Histology, University of Modena and Reggio Emilia, Modena, Italy.
Prata
Cecilia
C
Caliceti
Cristiana
C
Vieceli Dalla Sega
Francesco
F
Zambonin
Laura
L
Fiorentini
Diana
D
Hakim
Gabriele
G
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D047468:Immunoprecipitation; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human