Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level

Olivier Micheau (1) , Alexandre Morizot (1) , Delphine Mérino (1) , Najoua Lalaoui (1) , Guillaume Jacquemin (1) , Virginie Granci (1) , Elisabetta Iessi (1) , David Lanneau (1) , Florence Bouyer (1) , Eric Solary (1) , Bruno Chauffert (1) , Philippe Saas (1) , Carmen Garrido (1)

1 Mort Cellulaire et Cancer

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 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 TRAIL-R4's ability to cooperate with c-FLIP to inhibit TRAIL-induced cell death.

Mots clés: TRAIL; TRAIL-R4; c-FLIP; Chemotherapy; Apoptosis

Olivier Micheau, Alexandre Morizot, Delphine Mérino, Najoua Lalaoui, Guillaume Jacquemin, et al.. Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.144⟩. ⟨hal-00592295⟩