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TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress

2016; Impact Journals LLC; Volume: 8; Issue: 6 Linguagem: Inglês

10.18632/oncotarget.14285

1949-2553

Florent Dufour, Thibault Rattier, Andrei Constantinescu, Luciana Zischler, Aymeric Morlé, Hazem Ben Mabrouk, Étienne Humblin, Guillaume Jacquemin, Éva Szegezdi, Fabien Delacôte, Naziha Marrakchi, Gilles Guichard, Catherine Pellat‐Deceunynck, Pierre Vacher, Patrick Legembre, Carmen Garrido, Olivier Micheau,

RNA Interference and Gene Delivery

// Florent Dufour 1, 2 , Thibault Rattier 1, 2 , Andrei Alexandru Constantinescu 1, 2 , Luciana Zischler 1, 2, 3 , Aymeric Morlé 1, 2 , Hazem Ben Mabrouk 4 , Etienne Humblin 1, 2 , Guillaume Jacquemin 1, 2 , Eva Szegezdi 5 , Fabien Delacote 6 , Naziha Marrakchi 4 , Gilles Guichard 7 , Catherine Pellat-Deceunynck 8 , Pierre Vacher 9 , Patrick Legembre 10 , Carmen Garrido 1, 2, 11 , Olivier Micheau 1, 2, 11 1 INSERM, UMR866, « Equipe labellisée Ligue contre le Cancer » and Laboratoire d'Excellence LipSTIC, Dijon, France 2 Univ. Bourgogne Franche-Comté, Dijon, France 3 Pós-graduação emCiências da Saúde, Escola de Medicina, Pontifícia Univ. Católica do Paraná, Curitiba, Paraná, Brazil 4 Laboratoire des Venins et Biomolécules Thérapeutiques LR11IPT08, Institut Pasteur de Tunis, Tunis, Tunisia 5 Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland 6 Cellectis, Paris, France 7 Univ. de Bordeaux, CNRS, IPB, UMR 5248, CBMN, Institut Européen de Chimie et de Biologie, Pessac, France 8 INSERM, UMR892, CNRS 6299, Université de Nantes, Nantes, France 9 INSERM U1218, Univ. de Bordeaux, Institut Bergonié, Bordeaux, France 10 CLCC Eugène Marquis, INSERM ER440 Oncogenesis, Stress & Signaling, Rennes, France 11 Centre Georges-François Leclerc, Dijon, France Correspondence to: Micheau Olivier, email: olivier.micheau@inserm.fr Keywords: receptor, TRAIL, signaling, apoptosis, cancer Received: September 02, 2016 Accepted: November 30, 2016 Published: December 27, 2016 ABSTRACT TRAIL induces selective tumor cell death through TRAIL-R1 and TRAIL-R2. Despite the fact that these receptors share high structural homologies, induction of apoptosis upon ER stress, cell autonomous motility and invasion have solely been described to occur through TRAIL-R2. Using the TALEN gene-editing approach, we show that TRAIL-R1 can also induce apoptosis during unresolved unfolded protein response (UPR). Likewise, TRAIL-R1 was found to co-immunoprecipitate with FADD and caspase-8 during ER stress. Its deficiency conferred resistance to apoptosis induced by thaspigargin, tunicamycin or brefeldin A. Our data also demonstrate that tumor cell motility and invasion-induced by TRAIL-R2 is not cell autonomous but induced in a TRAIL-dependant manner. TRAIL-R1, on the other hand, is unable to trigger cell migration owing to its inability to induce an increase in calcium flux. Importantly, all the isogenic cell lines generated in this study revealed that apoptosis induced TRAIL is preferentially induced by TRAIL-R1. Taken together, our results provide novel insights into the physiological functions of TRAIL-R1 and TRAIL-R2 and suggest that targeting TRAIL-R1 for anticancer therapy is likely to be more appropriate owing to its lack of pro-motile signaling capability.