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.

Keywords: DR4; DR5; TRAIL; TRAIL-resistance; apoptosis; cancer.

Figure 1

Interaction of TRAIL with its five receptors (two agonostic receptors: DR4, DR5; and three antagonistic receptors: DcR1, DcR2, and OPG). Only the two agonistic receptors DR4 and DR5 can transduce the TRAIL induced cell death signaling.

Figure 2

Molecular details of canonical and non-canonical TRAIL signaling. Following TRAIL binding to its death receptors, the DISC can be formed which results in caspase-3 activation and apoptosis. A secondary complex can also be formed after TRAIL receptor activation, leading to the activation of various kinases and the induction of direct or indirect non-apoptotic responses as indicated (A). The ubiquitin–proteasome system can assist in the degradation of TRAIL-Rs (B).

Figure 3

Potential targets for sensitization of cancer cells to TRAIL induced apoptosis.