The observation that certain types of cancer express death receptors on their cell surface has triggered heightened interest in exploring the potential of receptor ligation as a novel anti-cancer modality, and since the expression is somewhat restricted to cancer cells the therapeutic implications are very promising. One such death receptor ligand belonging to the tumor necrosis receptor (TNF) superfamily, TNF-related apoptosis-inducing ligand (TRAIL), has been in the limelight as a tumor selective molecule that transmits death signal via ligation to its receptors (TRAIL-R1 and TRAIL-R2 or death receptors 4 and 5; DR4 and DR5). Interestingly, TRAIL-induced apoptosis exhibits hallmarks of extrinsic as well as intrinsic death pathways, and, therefore, is subject to regulation both at the cell surface receptor level as well as more downstream at the post-mitochondrial level. Despite the remarkable selectivity of DR expression on cancer cell surface, development of resistance to TRAIL-induced apoptosis remains a major challenge. Therefore, unraveling the cellular and molecular mechanisms of TRAIL resistance as well as identifying strategies to overcome this problem for an effective therapeutic response remains the cornerstone of many research endeavors. This review aims at presenting an overview of the biology, function and translational relevance of TRAIL with a specific view to discussing the various regulatory mechanisms and the current trends in reverting TRAIL resistance of cancer cells with the obvious implication of an improved clinical outcome.
2009 Elsevier Ltd. All rights reserved.