title: ER signaling regulation drives the switch between autophagy and apoptosis in NRK-52E cells exposed to cisplatin.
abstract: Cisplatin (cisPt) use in chemotherapy is limited by the occurrence of a severe nephrotoxicity. Both autophagy and apoptosis seem to contribute in kidney response to cisPt, however their cross-talk is still controversial, since the role played by autophagy (cytoprotective or harmful) and the cellular site driving their switch, are still unclear. Here, we used a multidisciplinary approach to study the correlation between autophagy and apoptosis in renal NRK-52E cells exposed to cisPt. We showed two "sensitivity-thresholds" to cisPt, stating whether apoptosis or autophagy would develop: 10 μM dose of cisPt activated autophagy that preserved cell homeostasis; however 3-methyladenine co-administration affected cell viability and induced apoptosis. In contrast, 50 μM cisPt determined cell death by apoptosis, whereas the pre-conditioning with taurine contributed to cell rescue, delaying apoptosis and maintaining autophagy. Hence, autophagy protects NRK-52E cells from cisPt injury. By studying the expression of ER specific hallmarks, such as GRP78, GRP94 and GADD153/CHOP, we found a possible pivotal role of ER signaling modulation in the crosstalk between autophagy and apoptosis induced by cisPt. To the best of our knowledge, this is the first demonstration that taurine enhances autophagic protection against apoptosis by reducing ER stress, thus making it possible to develop new strategies to reduce severe cisPt-induced side-effects such as nephrotoxicity.
authors.affiliation: Unit of Biochemistry, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy. rovetta@med.unibs.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Rovetta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Stacchiotti
authors.forename: Antonella
authors.initials: A
authors.lastname: Consiglio
authors.forename: Moris
authors.initials: M
authors.lastname: Cadei
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Grigolato
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavazza
authors.forename: Rita
authors.initials: R
authors.lastname: Rezzani
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Aleo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C018551:glucose-regulated proteins