Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level. - Archive ouverte HAL Access content directly
Journal Articles Cell Death and Differentiation Year : 2011

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

(1) , (1) , (1) , (1) , (1) , (1) , (1) , (1) , (1, 2) , (1, 3) , (4, 5) , (1) , (1, 3)
1
2
3
4
5

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
Vignette du fichier
CDD-10-0464_Morizot_.pdf (289.41 Ko) Télécharger le fichier
Vignette du fichier
Fig_6.pdf (50.44 Ko) Télécharger le fichier
Vignette du 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⟩
322 View
915 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More