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

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.

Coupling tumor necrosis factor‐related apoptosis‐inducing ligand to iron oxide nanoparticles increases its apoptotic activity on HCT116 and HepG2 malignant cells: effect of magnetic core size

“…Moreover, the specificity and the selectivity of NVs were assessed in HCT116 cells deficient for DR4 and DR5 (Dufour et al, ) (HCT116–DKO). In agreement with their selectivity towards TRAIL signaling and their lack of toxicity, neither NV10 nor NV100, even at high concentration (10 μg · mL −1 ), inhibited the viability of HCT116–DKO cells (Fig.…”

“…Tumor necrosis factor‐related apoptosis‐inducing ligand receptor‐deficient HCT116 (DKO) cells were generated by the TALEN approach, described by Dufour et al ().…”

Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo

“…24 Simultaneously, pro-caspase 8 binds to FADD and is activated as a result of dimer formation, which in turn, triggers activation of proteolytic cleavage effector caspases like caspase 3 that digest cellular proteins to induce apoptosis. 25 In our in vitro study, we found that the levels of DR4, DR5 and cleaved caspase 3 in pPB-SSL-TRAIL group were significantly higher than those in the groups treated with free rhTRAIL or SSL-TRAIL. The encapsulation of TRAIL in pPB-SSL delivery system did not seem to change how TRAIL functions, but rather made it easier for more TRAIL molecules to target aHSCs at their receptors.…”

Ligand nanovectorization using graphene to target cellular death receptors of cancer cell

“…Our work proposes to combine both static numeric methods (docking simulation) and dynamic simulations in order to accelerate the crea- between the TRAIL-based nanovector and DR4. 38 Comparatively, DR5 is able to trigger cell motility, invasion, and metastasis, but in a less pronounced way than DR4. 11,39 So far, it should be noted that authors generally hypothesized that DR5 plays a more important role than DR4 in triggering apoptosis in cells expressing both receptors.…”

“…To the best of our knowledge, this corresponds to the first evidence of such stability in a theoretical study. On the basis of recent findings, DR4 is the only true agonist receptor of TRAIL and could explain such complex stability between the TRAIL‐based nanovector and DR4 . Comparatively, DR5 is able to trigger cell motility, invasion, and metastasis, but in a less pronounced way than DR4 .…”