Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy

Abstract

(TNF)-related apoptosis-inducing ligand (TRAIL) is able to activate the extrinsic apoptotic pathway upon binding to DR4/TRAIL-R1 and/or DR5/TRAIL-R2 receptors. Structural data indicate that TRAIL functions as a trimer that can engage three receptor molecules simultaneously, resulting in receptor trimerization and leading to conformational changes in TRAIL receptors. However, receptor conformational changes induced by the binding of TRAIL depend on the molecular form of this death ligand, and not always properly trigger the apoptotic cascade. In fact, TRAIL exhibits a much stronger pro-apoptotic activity when is found as a transmembrane protein than when it occurs as a soluble form and this enhanced biological activity is directly linked to its ability to cluster TRAIL receptors in supra-molecular structures. In this regard, cells involved in tumor immunosurveillance, such as activated human T cells, secrete endogenous TRAIL as a transmembrane protein associated with lipid microvesicles called exosomes upon T-cell reactivation. Consequently, it seems clear that a proper oligomerization of TRAIL receptors, which leads to a strong apoptotic signaling, is crucial for inducing apoptosis in cancer cells upon TRAIL treatment. In this review, the current knowledge of oligomerization status of TRAIL receptors is discussed as well as the implications for cancer treatment when using TRAIL-based therapies.

Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B More Efficiently Than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors

“…It is possible that increased expression of death receptors on the cell surface promotes the formation of heterodimers where the receptors can be internalized together as part of the same DISC. This assumption is consistent with the fact that death receptors are capable of dimerization due to the interaction of N-terminal domains in the absence of ligands [26,27].…”

On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function

“…Experimental data support receptor oligomerization of TRAIL and other TNFRSF receptors on the cell surface but there have been conflicting models proposed over the years [4,6,13,14]. Activating several receptors all at once by their corresponding membrane-bound ligands necessitates that both the receptors and the ligands are arranged with the same geometry, which rules out random receptor/ligand arrangement on the cell surface.…”

“…In addition, because TRAIL provides an external trigger for apoptosis, it has the potential to overcome resistance to internal triggers of apoptosis after radiation or chemotherapy. There have been many excellent reviews on TRAIL biology and the mechanism of action with implication for therapeutic applications in recent years [2][3][4][5][6][7][8]. Here, we focus on the structure-function of TRAIL and extend our discussion to other members of the TNFSF/TNFRSF to illustrate the mechanism of signaling by reviewing the most up-to-date and relevant information from the scientific literature.…”

Stress Management: Death Receptor Signalling and Cross-Talks with the Unfolded Protein Response in Cancer

“…Multiple pre-existing or acquired cell death resistance mechanisms, such as caspase-8 mutations, cFLIP or anti-apoptotic Bcl-2 family members' overexpression, are also likely germane to these disappointing clinical results. Thus, several approaches to design TRAIL-R agonist-based therapies with improved pharmacological properties are underway (for reviews: [161][162][163][164]). TRAIL-R1 or -R2-specific agonistic antibodies have been developed too.…”