Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level. - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Cell Death and Differentiation Year : 2011

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

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.

Keywords

Fichier principal
Vignette du fichier
inserm-00525443_edited.pdf (565.9 Ko) Télécharger le fichier
CDD-10-0464_Morizot_.pdf (289.41 Ko) Télécharger le fichier
Fig_6.pdf (50.44 Ko) Télécharger le fichier
TRAIl-R4_September.pdf (2.42 Mo) Télécharger le fichier
Origin Files produced by the author(s)
Origin Files produced by the author(s)
Origin Files produced by the author(s)
Origin Files produced by the author(s)
Loading...

Dates and versions

inserm-00525443 , version 1 (18-05-2011)

Identifiers

Cite

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, 2011, 18 (4), pp.700-11. ⟨10.1038/cdd.2010.144⟩. ⟨inserm-00525443⟩
337 View
937 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More