title: Noxa couples lysosomal membrane permeabilization and apoptosis during oxidative stress.
abstract: The exact roles of lysosomal membrane permeabilization (LMP) in oxidative stress-triggered apoptosis are not completely understood. Here, we first studied the temporal relation between LMP and mitochondrial outer membrane permeabilization (MOMP) during the initial stage of apoptosis caused by the oxidative stress inducer H2O2. Despite its essential role in mediating apoptosis, the expression of the BH3-only Bcl-2 protein Noxa was dispensable for LMP. In contrast, MOMP was dependent on Noxa expression and occurred downstream of LMP. When lysosomal membranes were stabilized by the iron-chelating agent desferrioxamine, H2O2-induced increase in DNA damage, Noxa expression, and subsequent apoptosis were abolished by the inhibition of LMP. Importantly, LMP-induced Noxa expression increase was mediated by p53 and seems to be a unique feature of apoptosis caused by oxidative stress. Finally, exogenous iron loading recapitulated the effects of H2O2 on the expression of BH3-only Bcl-2 proteins. Overall, these data reveal a Noxa-mediated signaling pathway that couples LMP with MOMP and ultimate apoptosis during oxidative stress.
authors.affiliation: Molecular Targets Program, James Graham Brown Cancer Center, Departments of Medicine, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Colins O
authors.initials: CO
authors.lastname: Eno
authors.affiliation: Molecular Targets Program, James Graham Brown Cancer Center, Departments of Medicine, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Genes and Development Program, Metastasis Research Center, Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Avinashnarayan
authors.initials: A
authors.lastname: Venkatanarayan
authors.affiliation: School of Electronics and Information Engineering, Tongji University, Shanghai.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Genes and Development Program, Metastasis Research Center, Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Elsa R
authors.initials: ER
authors.lastname: Flores
authors.affiliation: Molecular Targets Program, James Graham Brown Cancer Center, Departments of Medicine, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA. Electronic address: chi.li@louisville.edu.
authors.forename: Chi
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D020552:Comet Assay; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C498702:PMAIP1 protein, human; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D006861:Hydrogen Peroxide
keywords: AO; Apoptosis; Bcl-2 proteins; DFO; H(2)O(2); Iron; LMP; Lysosomes; MEFs; MOMP; Oxidative stress; acridine orange; desferrioxamine; hydrogen peroxide; lysosomal membrane permeabilization; mitochondrial outer membrane permeabilization; mouse embryonic fibroblasts