Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptotic pathways in cancer immunosurveillance: molecular mechanisms and prospects for therapy

Abstract

Since first described in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has generated considerable interest as a cancer therapeutic because of its ability to induce apoptosis in a range of tumor cell types while having little activity on normal cells and tissues. Since then, the vast majority of studies published on TRAIL and anti-TRAIL receptor monoclonal antibodies have focused on the tumoricidal activity of these molecules, with the intention of developing TRAIL-receptor agonists into potent cancer therapeutic agents. As promising as these agonists have proved to be in vitro and in various in vivo preclinical models, there have been a number of obstacles identified likely contributing to the underwhelming clinical trial data obtained -including a high frequency of TRAIL-resistant tumors -and reduced excitement about using TRAIL-receptor agonists as monotherapy for cancer. Consequently, it is important to understand the various mechanisms used by tumor cells to maintain TRAIL resistance and develop novel combinatorial approaches to restore TRAIL sensitivity in tumor cells. This review highlights the complexities of the TRAIL-TRAIL-receptor system, explores various methods for inducing TRAIL-induced death of tumor cells, and discusses some of the mechanisms that regulate tumor resistance to TRAIL and the way in which this resistance can be countered.

Noncoding RNAs in apoptosis: identification and function

“…Overall, HOXA-AS1 acts as a repressor of apoptosis and TRAIL may be partially involved in this regulatory mechanism in ATRA-treated NB4 promyelocytic leukemia cells ( Zhao et al, 2013 ). Despite the potential use of TRAIL as a chemotherapeutic target, recent reports show the emergence of resistance of pancreatic cancer cells to TRAIL-induced apoptosis ( James and Griffith, 2014 ). HOTAIR is expressed at low levels in cells sensitive to the TRAIL-induced apoptosis while it exhibits high expression level in the resistant cells.…”