Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs | CU Experts

; Cytotoxic chemotherapy typically results in the elimination of a fraction of the tumor with surviving cells entering a state of persistence or premature replicative senescence that can lead to recurrence. Here, we show that therapy-induced senescence is associated with robust up-regulation of Fas and/or TRAIL-R2/DR5 death receptors in vitro and in vivo. The latter receptors restricted entry to senescence and exerted selective pressure on senescent cells through promoting assembly of proapoptotic receptor-interacting protein kinase 1 (RIPK1)/Fas-associated death domain protein (FADD)/Caspase-8 “FADDosome” complexes, restrained by cFLIP; L; . Accordingly, deletion of; CASP-8; robustly enhanced entry to senescence and prolonged the life span of senescent cells. cIAP-2, which inhibits death receptor–driven cell death, was also up-regulated in senescent cells, and deletion of IAPs suppressed entry to senescence. Consistent with this, small-molecule IAP antagonists exhibited potent senolytic activity through enhancing death receptor–initiated Caspase-8 activation. Thus, death receptor–driven assembly of RIPK1/FADD/Caspase-8 complexes in senescent cells orchestrates addiction to IAPs that can be exploited by IAP antagonists.;

Gunay G; Hamsici S; Venugopalan V; Costigan A; Fritsch M; Gallagher Aldave A; Huber A; Fernandez B; Efe-Cicek H; Davidovich P

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