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.
Highlights
TRAIL/APO2L selectively triggers cell death in a large variety of human tumors [1]
In order to get a better understanding of TRAIL-R1 and TRAIL-R2 specific signaling capabilities, we generated TRAIL receptor-deficient isogenic cell derivatives of the colorectal carcinoma cell line HCT116 using a Transcription activator-like effector nucleases (TALEN) gene editing approach
TRAIL-R1and/or TRAIL-R2-deficient cells were obtained after transfection and successive sorting of cells lacking TRAIL receptor expression by flow cytometry (Figure 1A-1D)
Summary
TRAIL/APO2L selectively triggers cell death in a large variety of human tumors [1]. This promising antitumor protein belongs to the TNF subfamily of apoptosisinducing ligands [2] and has attracted much interest in oncology. Apoptosis triggered by TRAIL occurs through its binding www.impactjournals.com/oncotarget to TRAIL-R1 and/or TRAIL-R2, coined DR4 and DR5, respectively [4] Activation of these cell surface receptors by TRAIL induces the formation of a socalled death-inducing signaling complex (DISC) on the cytosolic tail of the receptor, where the apoptosis-initiating caspase-8 and caspase-10 proteins are brought in close proximity by the adaptor protein FADD [5]. Recruitment of these two initiator caspases, through homotypic protein/ protein interactions within the TRAIL DISC, allows their activation and the subsequent release of their active cleaved forms to the cytosol where they activate by proteolytic cleavage effector caspases such as caspase-3, driving cell dismantling
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