ER signaling regulation drives the switch between autophagy and apoptosis in NRK-52E cells exposed to cisplatin

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.

► Both autophagy and apoptosis characterize renal cell response against the chemotherapic drug cisPt.
► Identified two “sensitivity-thresholds” to cisPt, where only apoptosis or autophagy will develop.
► Autophagy activation grants cytoprotection to renal cells.
► ER signaling plays a pivotal role in cisPt-induced switch between autophagy and apoptosis.
► ER stress modulators may enhance autophagic cell protective response against apoptosis.