title: TRAIL signals to apoptosis in chronic lymphocytic leukaemia cells primarily through TRAIL-R1 whereas cross-linked agonistic TRAIL-R2 antibodies facilitate signalling via TRAIL-R2.
abstract: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, which is being developed as an anti-tumour agent due to its selective toxicity to tumour cells, induces apoptosis by binding to two membrane-bound receptors, TRAIL-R1 and TRAIL-R2. Clinical trials have been initiated with various preparations of TRAIL as well as agonistic monoclonal antibodies to TRAIL-R1 and TRAIL-R2. Previously we reported that prior treatment of primary chronic lymphocytic leukaemia (CLL) cells with histone deacetylase inhibitors was required to sensitize CLL cells to TRAIL and, using various receptor-selective TRAIL mutant ligands, we demonstrated that CLL cells signalled to apoptosis primarily through TRAIL-R1. Some, but not all, agonistic TRAIL-receptor antibodies require cross-linking in order to induce apoptosis. The present study demonstrated that CLL cells can signal to apoptosis through the TRAIL-R2 receptor, but only after cross-linking of the agonistic TRAIL-R2 antibodies, LBY135 and lexatumumab (HGS-ETR2). In contrast, signalling through TRAIL-R1 by receptor-selective ligands or certain agonistic antibodies, such as mapatumumab (HGS-ETR1), occurs in the absence of cross-linking. These results further highlight important differences in apoptotic signalling triggered through TRAIL-R1 and TRAIL-R2 in primary tumour cells. Such information is clearly important for the rational optimisation of TRAIL therapy in primary lymphoid malignancies, such as CLL.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Natoni
authors.forename: Marion
authors.initials: M
authors.lastname: MacFarlane
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Renata
authors.initials: R
authors.lastname: Walewska
authors.forename: Aneela
authors.initials: A
authors.lastname: Majid
authors.forename: Deborah
authors.initials: D
authors.lastname: Knee
authors.forename: David R
authors.initials: DR
authors.lastname: Stover
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents; D004347:Drug Interactions; D036342:Ephrins / Q000502:physiology*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000077767:Panobinostat; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D003432:Cross-Linking Reagents; D036342:Ephrins; D006877:Hydroxamic Acids; D007211:Indoles; C000592141:LBY135 monoclonal antibody; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077767:Panobinostat; C510234:lexatumumab