Research Papers:

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

Florent Dufour _, Thibault Rattier, Andrei Alexandru Constantinescu, Luciana Zischler, Aymeric Morlé, Hazem Ben Mabrouk, Etienne Humblin, Guillaume Jacquemin, Eva Szegezdi, Fabien Delacote, Naziha Marrakchi, Gilles Guichard, Catherine Pellat-Deceunynck, Pierre Vacher, Patrick Legembre, Carmen Garrido and Olivier Micheau

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Oncotarget. 2017; 8:9974-9985. https://doi.org/10.18632/oncotarget.14285

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Florent Dufour1,2, Thibault Rattier1,2, Andrei Alexandru Constantinescu1,2, Luciana Zischler1,2,3, Aymeric Morlé1,2, Hazem Ben Mabrouk4, Etienne Humblin1,2, Guillaume Jacquemin1,2, Eva Szegezdi5, Fabien Delacote6, Naziha Marrakchi4, Gilles Guichard7, Catherine Pellat-Deceunynck8, Pierre Vacher9, Patrick Legembre10, Carmen Garrido1,2,11, Olivier Micheau1,2,11

1INSERM, UMR866, « Equipe labellisée Ligue contre le Cancer » and Laboratoire d’Excellence LipSTIC, Dijon, France

2Univ. Bourgogne Franche-Comté, Dijon, France

3Pós-graduação emCiências da Saúde, Escola de Medicina, Pontifícia Univ. Católica do Paraná, Curitiba, Paraná, Brazil

4Laboratoire des Venins et Biomolécules Thérapeutiques LR11IPT08, Institut Pasteur de Tunis, Tunis, Tunisia

5Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland

6Cellectis, Paris, France

7Univ. de Bordeaux, CNRS, IPB, UMR 5248, CBMN, Institut Européen de Chimie et de Biologie, Pessac, France

8INSERM, UMR892, CNRS 6299, Université de Nantes, Nantes, France

9INSERM U1218, Univ. de Bordeaux, Institut Bergonié, Bordeaux, France

10CLCC Eugène Marquis, INSERM ER440 Oncogenesis, Stress & Signaling, Rennes, France

11Centre 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


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.

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