Reticulon-1C acts as a molecular switch between endoplasmic reticulum stress and genotoxic cell death pathway in human neuroblastoma cells

Authors

  • Federica Di Sano,

    1. Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy
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    • The first two authors contributed equally to this paper.

  • Barbara Fazi,

    1. Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy
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    • The first two authors contributed equally to this paper.

  • Roberta Tufi,

    1. Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy
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  • Roberta Nardacci,

    1. National Institute for Infectious Diseases IRCCS ‘L. Spallanzani’, Via Portuense, Rome, Italy
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  • Mauro Piacentini

    1. Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy
    2. National Institute for Infectious Diseases IRCCS ‘L. Spallanzani’, Via Portuense, Rome, Italy
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Address correspondence and reprint requests to Mauro Piacentini, Department of Biology, University of Rome ‘Tor Vergata’, Via della Ricerca Scientifica 00133 Rome, Italy. E-mail: mauro.piacentini@uniroma2.it

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 Ca2+ 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 Ca2+, 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.

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