TRAIL‐Induced Caspase Activation Is a Prerequisite for Activation of the Endoplasmic Reticulum Stress‐Induced Signal Transduction Pathways

Abstract

It is well known that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis can be initially triggered by surface death receptors (the extrinsic pathway) and subsequently amplified through mitochondrial dysfunction (the intrinsic pathway). However, little is known about signaling pathways activated by the TRAIL-induced endoplasmic reticulum (ER) stress response. In this study, we report that TRAIL-induced apoptosis is associated with the endoplasmic reticulum (ER) stress response. Human colorectal carcinoma HCT116 cells were treated with TRAIL and the ER stress-induced signal transduction pathway was investigated. During TRAIL treatment, expression of ER stress marker genes, in particular the BiP (binding immunoglobulin protein) gene, was increased and activation of the PERK (PKR-like ER kinase)-eIF2α (eukaryotic initiation factor 2α)-ATF4 (activating transcription factor 4)-CHOP (CCAAT-enhancer-binding protein homologous protein) apoptotic signal transduction pathway occurred. Experimental data from use of a siRNA (small interfering RNA) technique, caspase inhibitor, and caspase-3-deficient cell line revealed that TRAIL-induced caspase activation is a prerequisite for the TRAIL-induced ER stress response. TRAIL-induced ER stress was triggered by caspase-8-mediated cleavage of BAP31 (B cell receptor-associated protein 31). The involvement of the proapoptotic PERK-CHOP pathway in TRAIL-induced apoptosis was verified by using a PERK knockout (PERK(-/-)) mouse embryo fibroblast (MEF) cell line and a CHOP(-/-) MEF cell line. These results suggest that TRAIL-induced the activation of ER stress response plays a role in TRAIL-induced apoptotic death.

Developing TRAIL/TRAIL death receptor-based cancer therapies

“…Loss of ATF4, ATF3, or CHOP reduced the DR5 levels and decreased apoptosis [29]. Alternately, TRAIL can induce ER stress via caspase-8-mediated cleavage of B cell receptor-associated protein 31 (BAP31) [30]. Increased production of reactive oxygen species (ROS) can regulate TRAIL signaling by ROS-ERK-CHOP-mediated up-regulation of DR4 and DR5 expression [31].…”

The regulation of combined treatment-induced cell death with recombinant TRAIL and bortezomib through TRAIL signaling in TRAIL-resistant cells

“…Bortezomib induces ER (endoplasmic reticulum) stress, and the proteins that induce this stress are known to increase TRAIL-sensitivity in some cells [ 41 , 42 ]. Thus, ER stress related proteins were up-regulated by bortezomib treatment in CT26 and B16F10 cells, however the cell death induced by the combined treatment was not influenced by the addition of ER stress inhibitors in CT26 and B16F10 cells (Additional file 5 : Figure S5).…”

“…This may be due to inhibition of the reactivity of the XTT substrate by SP600125. The ER stress response and JNK activation have been reported as either positive or negative regulators of TRAIL-induced cell death in several cells; however, the combination treatment-induced cell death in B16F10 and CT26 cells was not regulated by the ER stress response, autophagy, or JNK activation [ 42 , 45 – 48 ].…”

N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis

“…They generate a large number of proteolytic cleavage products bearing the Nt-Arg or arginylation-permissive residues. The expression and activity of some proteases are enhanced under stresses that involve the misregulation of proteostasis such as ER stress, oxidative stress, and proteasomal inhibition (24). Overall, these diverse types of proteolytic cleavage products generate a pool of Nt-arginylated substrates exposing Nt-Arg.…”