Reticulon-1C acts as a molecular switch between endoplasmic reticulum stress and genotoxic cell death pathway in human neuroblastoma cells.
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.
Di Sano
Federica
F
Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy.
Fazi
Barbara
B
Tufi
Roberta
R
Nardacci
Roberta
R
Piacentini
Mauro
M
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
D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C081781:RTN1 protein, human; D016159:Tumor Suppressor Protein p53