Abstract
Besides its tumor-selective apoptotic activity, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes pro-survival, proliferative or migratory signaling (NF-κB, PI3K/Akt, MAPK and JNK; referred to as 'non-apoptotic' cascades). Indeed, apoptosis and non-apoptotic signaling can be activated in clonal populations of cancer cells in response to treatment and, as a result, only a part of the initial cellular population dies while a fraction survives and develops resistance to TRAIL-induced apoptosis (referred to as 'fractional survival'). Notably, the molecular characterization of the protein platforms streaming into tumoricidal versus tumor-promoting cascades that control fractional survival remained elusive. Here we demonstrate that, in the context of DR4–DR5–DcR2 hetero-oligomeric complexes, a single death receptor (DR5) suffices to assemble composite plasma membrane-proximal pro-apoptotic/pro-survival platforms that propagate TRAIL signaling to both death and survival pathways in clonal populations of cancer cells. Moreover, we show that while all members of TRAIL-induced complexes support survival, none of them acted exclusively pro-apoptotic. Indeed, key apoptotic proteins as FADD and procaspase-8 were also involved in transducing non-apoptotic signaling in response to this cytokine. Collectively, this study reveals the Janus faces of DR5, and the contributions of other death complex components in fractional survival that foster the generation of resistance. Our data highlight a new level of complexity in TRAIL signaling and point to an improved therapeutic rationale in view of hitherto disappointing results.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, TNFSF10, Apo2L), a member of the tumor necrosis factor family of cytokines, binds to the extracellular domains of four plasma membrane-bound receptors inducing their oligomerization
We demonstrate that a single death receptor (DR5) and central death inducing signaling complex (DISC) components (FADD and caspase-8) form the core of composite pro-apoptotic-pro-survival plasma membrane-proximal platform(s) that lead to apoptosis but concomitantly activate non-apoptotic cascades, thereby supporting establishment of reversible resistance in cancer
To study the molecular mechanisms underlying fractional survival in response to TRAIL treatment, we used isogenic populations of cancer cells derived from stepwise tumorigenesis models, in which normal cells are transformed into tumorigenic ones by introducing defined genetic elements.[34,35]
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, TNFSF10, Apo2L), a member of the tumor necrosis factor family of cytokines, binds to the extracellular domains of four plasma membrane-bound receptors inducing their oligomerization. TRAIL activates nonapoptotic cascades[23] in non-tumorigenic scenarios, in populations of cancer cells fully resistant to TRAIL-induced cell death and in processes of fractional survival.[12,24,25,26,27,28,29,30,31] In that regard, activation of TRAIL-induced non-apoptotic cascades has been ascribed to the formation of a signaling complex (referred to as 'secondary complex') composed of FADD, caspase-8, RIPK1 (receptor-interacting serine/threonine-protein kinase 1), TRAF2 (TNF receptor-associated factor 2) and NEMO/IKK (NF-κ-B essential modulator).[23] Yet, it remains unclear whether this complex is an entity entirely distinct from the DISC, as the subcellular compartment(s) where TRAIL-induced signaling complex(es) is/are formed and the role of individual TRAIL receptors in the assembly of such platform(s) are largely unknown. Our results are of major importance for the implementation of TRAIL-based cancer-selective therapies and provide a new rationale for the rather disapointing results obtained with TRAIL-therapeutics.[32,33]
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