0000000000243087
AUTHOR
Guillaume Jacquemin
Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level
International audience; 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 ma…
dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8
Toll-like receptor 3 (TLR3) is a pattern-recognition receptor known to initiate an innate immune response when stimulated by double-stranded RNA (dsRNA). Components of TLR3 signaling, including TIR domain-containing adapter inducing IFN-α (TRIF), have been demonstrated to contribute to dsRNA-induced cell death through caspase-8 and receptor interacting protein (RIP)1 in various human cancer cells. We provide here a detailed analysis of the caspase-8 activating machinery triggered in response to Poly(I:C) dsRNA. Engagement of TLR3 by dsRNA in both type I and type II lung cancer cells induces the formation of an atypical caspase-8-containing complex that is devoid of classical death receptors…
TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT.
International audience; BACKGROUND: TRAIL/Apo2L is a pro-apoptotic ligand of the TNF family that engages the apoptotic machinery through two pro-apoptotic receptors, TRAIL-R1 and TRAIL-R2. This cell death program is tightly controlled by two antagonistic receptors, TRAIL-R3 and TRAIL-R4, both devoid of a functional death domain, an intracellular region of the receptor, required for the recruitment and the activation of initiator caspases. Upon TRAIL-binding, TRAIL-R4 forms a heteromeric complex with the agonistic receptor TRAIL-R2 leading to reduced caspase-8 activation and apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We provide evidence that TRAIL-R4 can also exhibit, in a ligand independent…
Mécanismes de résistance à l'apoptose induite par TRAIL dans les cellules cancéreuses : restauration de la sensibiltié à TRAIL par la chimiothérapie conventionnelle ou par un polyphénol, la quercétine
The TNF-family member TRAIL (TNF-related apoptosis inducing ligand) is a cytokine involved in immune anti-tumour surveillance. TRAIL is one of the most promising agents currently under investigation, as it exhibits efficient anti-cancer cytotoxicity with limited side effects on healthy cells. The problem in current cancer therapy is that some cancer cells are already resistant, or can become resistant to TRAIL-induced cell death. The aim of my thesis was to study the mechanisms of resistance to TRAIL, and to find a way to bypass it. First, we were interested in the TRAIL-R4 antagonistic receptor, which is known to bind TRAIL without inducing a death signal. We have demonstrated for the firs…