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Review
. 2015 Nov:155:117-31.
doi: 10.1016/j.pharmthera.2015.09.001. Epub 2015 Sep 5.

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

Gustavo P Amarante-Mendes  1 , Thomas S Griffith  2
Affiliations
Review

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

Gustavo P Amarante-Mendes et al. Pharmacol Ther. 2015 Nov.

Abstract

TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future.

Keywords: Apoptosis; Cancer; Cell death; Immune therapy; TRAIL.

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Conflict of interest statement

Conflict of interest

“The authors declare that there are not conflicts of interest.”

Figures

Fig. 1
Fig. 1
TRAIL/Apo2L, its receptors and cell death signaling pathways. TRAIL/Apo2L is a trimeric protein able to associate with five different proteins that may act as transducer of cell death and other signals (DR4/TRAIL-R1 and DR5/TRAIL-R2) or non-signaling, decoy receptors (DcR1/TRAIL-R3, DcR2/TRAIL-R4 and OPG) that act as inhibitory molecules. Binding of TRAIL/Apo2L to trimeric forms of DR4/TRAIL-R1 or DR5/TRAIL-R2 at the cell membrane leads to a high molecular weight receptor cluster formation responsible for recruitment of FADD and pro-caspase-8/10 to assemble the Death-Inducing Signaling Complex (DISC). Active caspase-8 can subsequently cleave the effector caspases-3/-6/-7 in Type I cells or process the BH3-only member BID in Type II cells. The truncated form of BID (tBID) translocates to the mitochondria and, via BAX and BAK, induces Mitochondria Outer Membrane Permeabilization (MOMP) and consequent release of apoptogenic factors to the cytosol. Cytochrome c catalyzes the assembly of the Apoptosome, a multimolecular platform comprised of APAF-1 and procaspase-9. Similarly to caspase-8, caspase-9 processes and activates the effector caspases, culminating in apoptosis. The release of SMAC/Diablo from the mitochondria to the cytosol results in inactivation of members of the Inhibitor of Apoptosis Protein (IAP) family, particularly XIAP, an endogenous inhibitor of caspases, thereby facilitating apoptosis. TRAIL-induced apoptosis can be blocked at the DISC by cFLIP, a caspase-8/10 homologous protein that lacks enzymatic activity. Under particular circumstances, such as deficiency in caspase-8, an alternative cell death-inducing complex called necroptosome and composed by RIPK1, RIPK3 and the pseudokinase MLKL is formed, leading to necroptosis.
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