title: Intracellular cysteine oxidation is modulated by aquaporin-8-mediated hydrogen peroxide channeling in leukaemia cells.
abstract: The modulation of H2O2production by NADPH oxidase (Nox), on vascular endothelial growth factor (VEGF) stimulation, affects the redox signaling linked to cancer cell proliferation. H2O2signal transduction involves reversible oxidation of thiol proteins, leading to the formation of cysteine sulfenic acids, responsible for the temporary inactivation of many phosphatases. These events imply that H2O2reaches its intracellular targets. As Aquaporin-8 (AQP8) has been demonstrated to funnel Nox-produced H2O2across the plasma membrane, this study aims to elucidate the role of AQP8 in the redox signaling occurring in human leukaemia B1647 cells that constitutively produce VEGF. AQP8 overexpression or silencing resulted in the modulation of VEGF ability of increasing or decreasing, respectively, H2O2intracellular level. Moreover, data obtained by a dimedone-based immunochemical method for sulfenic acid detection demonstrate that the expression of AQP8 can modulate the amplitude of downstream events, altering the activity of redox-sensitive targets. In particular, AQP8 affected VEGF-induced redox signaling by increasing the sulfenation of the tumor suppressor PTEN, which resulted in its inactivation and, in turn, caused Akt activation. Therefore, the dimedone-based method for easily monitoring cellular protein sulfenation allowed to demonstrate, for the first time, the role of AQP8 on the fine tune of cysteine oxidation in target proteins involved in leukaemia cell proliferation pathways. © 2016 BioFactors, 43(2):232-242, 2017.
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Bologna, Italy.|Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vieceli Dalla Sega
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Prata
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Zambonin
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Angeloni
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Rizzo
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Hrelia
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Fiorentini
mesh_terms: D020346:Aquaporins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000008:administration & dosage; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism*; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D020346:Aquaporins; D003512:Cyclohexanones; D017382:Reactive Oxygen Species; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C108330:aquaporin 8; C004774:dimedone; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D003545:Cysteine; C013461:cysteine sulfinic acid
keywords: NAD(P)H oxidase; aquaporin; hydrogen peroxide; leukaemia cells; oxidized cysteines; redox signaling