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.
Highlights
Pre-existing or acquired resistance to chemotherapy is a major obstacle in effective cancer therapy, as it often leads to the therapy failure and the disease relapse [1]
DR5 up-regulation Up-regulation of DR5 and inactivation of DNA-dependent protein kinase (DNA-PK)/Akt, a pathway required for cancer cell metastasis Stabilizing tBid and Bik Modulating the interaction of Fas-associated death domain (FADD) and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors A caspase-dependent, E6-independent mechanism Increased in activation of caspase-8 in the death-inducing signaling complex p53-independent DR5 up-regulation PKCε-dependent down-regulation of AKT and X-linked inhibitor of apoptosis protein (XIAP) expressions Inhibiting the nuclear factor kappa B (NF-κB) signaling pathway
The dogged pursuit of validating TRAIL as a specific anti-cancer agent has further highlighted its limitations in the clinical setting
Summary
Cell Death Research Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India. Various molecular targets leading toTRAIL resistance are wellstudied, 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 theTRAIL sensitivity and combination therapies with such compounds may resensitize TRAIL resistant cancer cells toward TRAIL-induced apoptosis. We have summarized the key cellular processes associated with TRAIL resistance and their status as therapeutic targets for novel TRAIL-sensitizing agents
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