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.
Highlights
Apo2 Ligand/TNF-Related Apoptosis Inducing Ligand (Apo2L/TRAIL) was initially described as a TNF family member able to induce apoptosis in a wide range of tumor cells while sparing normal cells [1,2]
Recent clinical trials suggest that combination treatments with cytotoxic drugs and TRAIL receptor-targeted agents do not provide additional benefit compared to cytotoxic agents alone [8,9]
This review summarizes, the current data on the relationship between oligomerization status of TRAIL receptors and bioactivity and the implications for the potential application of TRAIL-based therapy in cancer as well as the main novel TRAIL-based formulations that are currently being developed
Summary
Apo Ligand/TNF-Related Apoptosis Inducing Ligand (Apo2L/TRAIL) was initially described as a TNF family member able to induce apoptosis in a wide range of tumor cells while sparing normal cells [1,2] This observation lead to the belief that TRAIL could behave as a promising selective anti-tumor agent and Phase I/II clinical trials were undertaken using TRAIL-based therapeutic agents [3,4]. Many factors contributed to TRAIL resistance and, to the lack of clinical efficacy of TRAIL-based therapies such as the use of weak TRAIL receptors agonists In this regard, it has been described that death ligands exhibit a stronger activity when they occur as transmembrane proteins rather than in their soluble form, and this enhanced killing activity is directly linked to their ability to aggregate and arrange their specific receptors in supra-molecular clusters [5]. This review summarizes, the current data on the relationship between oligomerization status of TRAIL receptors and bioactivity and the implications for the potential application of TRAIL-based therapy in cancer as well as the main novel TRAIL-based formulations that are currently being developed
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