title: Reticulon-1C acts as a molecular switch between endoplasmic reticulum stress and genotoxic cell death pathway in human neuroblastoma cells.
abstract: Damage or stress in many organelles may trigger apoptosis by several not yet fully elucidated mechanisms. A cell death pathway is induced by endoplasmic reticulum (ER) stress elicited by the unfolded protein response and/or by aberrant Ca(2+) signalling. Reticulon-1C (RTN-1C) belongs to the reticulon family, neuroendocrine-specific proteins localized primarily on the ER membrane. In the present study, we demonstrate that RTN-1C is able to modulate, in a mutually exclusive way, the cellular sensitivity to different apoptosis pathways in human neuroblastoma cells. In fact, the increase of RTN-1C protein levels per se results in ER stress-induced cell death, mediated by an increase of cytosolic Ca(2+), and significantly sensitizes cells to different ER stress inducers. In line with these findings, the reduction of RTN-1C, by antisense DNA expression, reduced the sensitivity to ER-stressors. In the presence of high RTN-1C levels, genotoxic drugs become ineffective as a consequence of the cytoplasm translocation of p53 protein, while the silencing of endogenous RTN-1C results in the potentiation of the genotoxic drugs action. These data indicate that RTN-1C is able to modulate the cellular sensitivity to different apoptotic pathways representing a promising molecular target for new drug development.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Sano
authors.forename: Barbara
authors.initials: B
authors.lastname: Fazi
authors.forename: Roberta
authors.initials: R
authors.lastname: Tufi
authors.forename: Roberta
authors.initials: R
authors.lastname: Nardacci
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C081781:RTN1 protein, human; D016159:Tumor Suppressor Protein p53