![]() However, TRAIL-based agents exhibited a limited anti-tumor activity and many primary human tumors were resistant to monotherapy with recombinant soluble TRAIL and other TRAIL receptors agonists. This observation lead to the belief that TRAIL could behave as a promising selective anti-tumor agent and in fact, Phase I/II clinical trials were undertaken using TRAIL-based therapeutic agents. 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.Īpo2 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. 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 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. 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. 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. 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. ![]() (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. ![]()
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