Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level.: Chemotherapy overcomes TRAIL-R4 inhibition

Abstract : TNF-related apoptosis-inducing ligand or Apo2L (Apo2L/TRAIL) is a promising anti-cancer drug owing to its ability to trigger apoptosis by binding to TRAIL-R1 or TRAIL-R2, two membrane-bound receptors that are often expressed by tumor cells. TRAIL can also bind non-functional receptors such as TRAIL-R4, but controversies still exist regarding their potential to inhibit TRAIL-induced apoptosis. We show here that TRAIL-R4, expressed either endogenously or ectopically, inhibits TRAIL-induced apoptosis. Interestingly, the combination of chemotherapeutic drugs with TRAIL restores tumor cell sensitivity to apoptosis in TRAIL-R4-expressing cells. This sensitization, which mainly occurs at the death-inducing signaling complex (DISC) level, through enhanced caspase-8 recruitment and activation, is compromised by c-FLIP expression and is independent of the mitochondria. Importantly, TRAIL-R4 expression prevents TRAIL-induced tumor regression in nude mice, but tumor regression induced by TRAIL can be restored with chemotherapy. Our results clearly support a negative regulatory function for TRAIL-R4 in controlling TRAIL signaling, and unveil the ability of TRAIL-R4 to cooperate with c-FLIP to inhibit TRAIL-induced cell death.
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Cell Death and Differentiation, Nature Publishing Group, 2011, 18 (4), pp.700-11. 〈10.1038/cdd.2010.144〉
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Alexandre Morizot, Delphine Mérino, Najoua Lalaoui, Guillaume Jacquemin, Virginie Granci, et al.. Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level.: Chemotherapy overcomes TRAIL-R4 inhibition. Cell Death and Differentiation, Nature Publishing Group, 2011, 18 (4), pp.700-11. 〈10.1038/cdd.2010.144〉. 〈inserm-00525443〉

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