| Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level. | |
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MedLine Citation:
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PMID: 21072058 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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A Morizot; D Mérino; N Lalaoui; G Jacquemin; V Granci; E Iessi; D Lanneau; F Bouyer; E Solary; B Chauffert; P Saas; C Garrido; O Micheau |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-12 |
Journal Detail:
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Title: Cell death and differentiation Volume: 18 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-14 Completed Date: 2011-07-11 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 700-11 Citation Subset: IM |
Copyright Information:
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© 2011 Macmillan Publishers Limited |
Affiliation:
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INSERM, U866, Dijon, F-21079 France [2] Faculty of Medicine and Pharmacy, Université de Bourgogne, Dijon, F-21079, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Combined Chemotherapy Protocols
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pharmacology* Apoptosis CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism Caspase 8 / metabolism Cell Line, Tumor Death Domain Receptor Signaling Adaptor Proteins / metabolism* Drug Resistance, Neoplasm GPI-Linked Proteins / metabolism Humans Models, Biological Neoplasms / drug therapy RNA Interference RNA, Small Interfering / metabolism Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism TNF-Related Apoptosis-Inducing Ligand / administration & dosage, pharmacology* Tumor Necrosis Factor Decoy Receptors / antagonists & inhibitors, genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/CFLAR protein, human; 0/Death Domain Receptor Signaling Adaptor Proteins; 0/GPI-Linked Proteins; 0/RNA, Small Interfering; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFRSF10B protein, human; 0/TNFRSF10C protein, human; 0/TNFRSF10D protein, human; 0/Tumor Necrosis Factor Decoy Receptors; EC 3.4.22.-/Caspase 8 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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