Abstract
Rapidly developing resistance against different therapeutics is a major stumbling block in the standardization of therapy. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated signaling has emerged as one of the most highly and extensively studied signal transduction cascade that induces apoptosis in cancer cells. Rapidly emerging cutting-edge research has helped us to develop a better understanding of the signaling machinery involved in inducing apoptotic cell death. However, excitingly, cancer cells develop resistance against TRAIL-induced apoptosis through different modes. Loss of cell surface expression of TRAIL receptors and imbalance of stoichiometric ratios of pro- and anti-apoptotic proteins play instrumental roles in rewiring the machinery of cancer cells to develop resistance against TRAIL-based therapeutics. Natural products have shown excellent potential to restore apoptosis in TRAIL-resistant cancer cell lines and in mice xenografted with TRAIL-resistant cancer cells. Significantly refined information has previously been added and continues to enrich the existing pool of knowledge related to the natural-product-mediated upregulation of death receptors, rebalancing of pro- and anti-apoptotic proteins in different cancers. In this mini review, we will set spotlight on the most recently published high-impact research related to underlying mechanisms of TRAIL resistance and how these deregulations can be targeted by natural products to restore TRAIL-mediated apoptosis in different cancers.
Highlights
Cancer is a multifaceted and therapeutically challenging disease
There was substantial evidence highlighting the presence of DR5 in the autophagosomes, followed by degradation by lysosomes [17]. These findings clearly suggest that circulating tumor cells (CTCs) escape from TNF-Related Apoptosis-Inducing Ligand (TRAIL)-mediated killing activities by reducing the cell surface expression of DR5
The cancer genome atlas (TCGA) network groups have comprehensively reported the genomic landscape for over 30 different cancer types [46]. Many of these malignancies have a subset of cases which harbored genomic alterations in components of extrinsic or intrinsic pathways, including overexpression and amplification of FADD and inhibitors of apoptotic proteins (IAPs), as well as the identification of mutations in caspase-encoding genes [47,48]
Summary
Cancer is a multifaceted and therapeutically challenging disease. Groundbreaking discoveries in the past few decades have enabled us to develop a sharper understanding of intra- and inter-tumor heterogeneity, loss of apoptosis, oncogenic overexpression, inactivation of tumor suppressors, and deregulation of spatio-temporally controlled signal transduction cascades which play a central role in cancer onset and progression [1,2,3,4]. 2. Molecular Insights of TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Signaling. When the signaling is “switched on”, it results in the activation of downstream effector molecules for both pathways that mediate apoptosis. A wealth of information points towards myriad signaling pathways which crosstalk with different proteins of the TRAIL-mediated signaling pathway, and play a critical role. D201o9u, 2r0,r2e0v10iew into negative and positive regulators of TRAIL-mediated signaling 3toof 13 comprehensively analyze the most recent breakthroughs made in uncovering mechanisms that inhibit or potentiate TRAIL-triggered apoptotic cell death. Either caspase-8 can activate its downstream effector caspases or it can proteolytically process the Bid protein to initialize the intrinsic pathway that routes through mitochondria. We partitioned our review into negative and positive regulators of TRAIL-mediated signaling to comprehensively analyze the most recent breakthroughs made in uncovering mechanisms that inhibit or potentiate TRAIL-triggered apoptotic cell death
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