title: Revealing mechanisms of selective, concentration-dependent potentials of 4-hydroxy-2-nonenal to induce apoptosis in cancer cells through inactivation of membrane-associated catalase.
abstract: Tumor cells generate extracellular superoxide anions and are protected against superoxide anion-mediated intercellular apoptosis-inducing signaling by the expression of membrane-associated catalase. 4-Hydroxy-2-nonenal (4-HNE), a versatile second messenger generated during lipid peroxidation, has been shown to induce apoptosis selectively in malignant cells. The findings described in this paper reveal the strong, concentration-dependent potential of 4-HNE to specifically inactivate extracellular catalase of tumor cells both indirectly and directly and to consequently trigger apoptosis in malignant cells through superoxide anion-mediated intercellular apoptosis-inducing signaling. Namely, 4-HNE caused apoptosis selectively in NOX1-expressing tumor cells through inactivation of their membrane-associated catalase, thus reactivating subsequent intercellular signaling through the NO/peroxynitrite and HOCl pathways, followed by the mitochondrial pathway of apoptosis. Concentrations of 4-HNE of 1.2 µM and higher directly inactivated membrane-associated catalase of tumor cells, whereas at lower concentrations, 4-HNE triggered a complex amplificatory pathway based on initial singlet oxygen formation through H2O2 and peroxynitrite interaction. Singlet-oxygen-dependent activation of the FAS receptor and caspase-8 increased superoxide anion generation by NOX1 and amplification of singlet oxygen generation, which allowed singlet-oxygen-dependent inactivation of catalase. 4-HNE and singlet oxygen cooperate in complex autoamplificatory loops during this process. The finding of these novel anticancer pathways may be useful for understanding the role of 4-HNE in the control of malignant cells and for the optimization of ROS-dependent therapeutic approaches including antioxidant treatments.
authors.affiliation: Institute of Virology, Department of Medical Microbiology and Hygiene, University of Freiburg, D-79104 Freiburg, Germany. Electronic address: georg.bauer@uniklinik-freiburg.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Bauer
authors.affiliation: LabOS, Rudjer Boskovic Institute, HR-10000 Zagreb, Croatia; University of Applied Sciences, Baltazar, HR-10290 Zapresic, Croatia.
authors.forename: Neven
authors.initials: N
authors.lastname: Zarkovic
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D002374:Catalase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009928:Organ Specificity; D030421:Peroxynitrous Acid / Q000378:metabolism; D026082:Singlet Oxygen / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000447:Aldehydes; D019014:fas Receptor; D013481:Superoxides; D030421:Peroxynitrous Acid; D026082:Singlet Oxygen; D009569:Nitric Oxide; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D053181:Caspase 8; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxy-2-nonenal; Apoptosis; Caspase-8; Catalase; Free radicals; HOCl signaling; NADPH oxidase; NO/peroxynitrite signaling; Singlet oxygen; Superoxide anion-mediated intercellular apoptosis-inducing signaling