Trailing TRAIL Resistance: Novel Targets for TRAIL Sensitization in Cancer Cells

Abstract

Resistance to chemotherapeutic drugs is the major hindrance in the successful cancer therapy. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family of ligands, which initiates apoptosis in cancer cells through interaction with the death receptors DR4 and DR5. TRAIL is perceived as an attractive chemotherapeutic agent as it specifically targets cancer cells while sparing the normal cells. However, TRAIL therapy has a major limitation as a large number of the cancer develop resistance toward TRAIL and escape from the destruction by the immune system. Therefore, elucidation of the molecular targets and signaling pathways responsible for TRAIL resistance is imperative for devising effective therapeutic strategies for TRAIL resistant cancers. Although, various molecular targets leading to TRAIL resistance are well-studied, recent studies have implicated that the contribution of some key cellular processes toward TRAIL resistance need to be fully elucidated. These processes primarily include aberrant protein synthesis, protein misfolding, ubiquitin regulated death receptor expression, metabolic pathways, epigenetic deregulation, and metastasis. Novel synthetic/natural compounds that could inhibit these defective cellular processes may restore the TRAIL sensitivity and combination therapies with such compounds may resensitize TRAIL resistant cancer cells toward TRAIL-induced apoptosis. In this review, we have summarized the key cellular processes associated with TRAIL resistance and their status as therapeutic targets for novel TRAIL-sensitizing agents.

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

“…One of the most important aspects considered when designing therapeutic approaches using TRAIL receptor agonists is the diversity of mechanisms that can award resistance to TRAIL-mediated cell death (So et al, 2015; Trivedi & Mishra, 2015; Twomey et al, 2015). We have already mentioned the existence of the Decoy Receptors (DcR1/TRAIL-R3, DcR2/TRAIL-R4 and OPG), which can bind to TRAIL but are unable to activate either the apoptotic or necroptotic signaling cascade.…”

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

“…To ameliorate TRAIL activity, several formulations of recombinant TRAIL, such as fusion to poly-histidine, Flag and leucin Zipper tags, or linked to Fc portion of IgG, have been developed and are currently tested at preclinical level (6,7). The combination of recombinant TRAIL with chemotherapeutics, radiotherapy, small molecules, or natural compounds aimed at enhancing the sensitivity of cancer cells, have also found wide application in preclinical approaches (8,9). In addition, liposomes, mesenchymal stem cells, leukocytes, or engineered CD34…”

Gold nanoparticles enhance TRAIL sensitivity through Drp1-mediated apoptotic and autophagic mitochondrial fission in NSCLC cells

“…7 Accordingly, tremendous efforts have been made to clarify the mechanisms responsible for the resistance to TRAIL, and development of TRAIL-based combinatorial approaches is considered to be one of the most promising therapeutic strategies for cancer treatment. 8,33,34 In this study, we investigated whether AuNPs could modulate TRAIL sensitivity in NSCLC in vitro and in vivo toward the goal of providing new therapeutic options to treat refractory NSCLC. Here, we demonstrated that AuNPs enhance TRAIL-induced apoptosis in NSCLC by modulating mitochondrial dynamics, and TRAIL combined with AuNPs performs as an effective chemotherapeutic strategy for NSCLC.…”