title: Role of tumor necrosis factor-related apoptosis-inducing ligand in interferon-induced apoptosis in human bladder cancer cells.
abstract: Immunomodulators such as Bacillus Calmette-Guerin and interferon are clinically active in transitional cell carcinoma of the bladder, but their mechanisms of action remain unclear. Here we investigated the effects of IFNalpha on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and apoptosis in a panel of 20 human bladder cancer cell lines. Six (30%) displayed significant DNA fragmentation in response to increasing concentrations of IFNalpha (10-100,000 units/mL). In these lines IFNalpha induced early activation of caspase-8, and DNA fragmentation was blocked by a caspase-8-selective inhibitor (IETDfmk), consistent with the involvement of death receptor(s) in cell death. IFNalpha stimulated marked increases in TRAIL mRNA and protein in the majority of IFN-sensitive and IFN-resistant cell lines. A blocking anti-TRAIL antibody significantly inhibited IFN-induced DNA fragmentation in four of six IFN-sensitive cell lines, confirming that TRAIL played a direct role in cell death. Bortezomib (PS-341, Velcade), a potent TRAIL-sensitizing agent, increased sensitivity to IFNalpha in two of the IFN-resistant cell lines that produced large amounts of TRAIL in response to IFN treatment. Our data show that IFN-induced apoptosis in bladder cancer cells frequently involves autocrine TRAIL production. Combination therapy strategies aimed at overcoming TRAIL resistance may be very effective in restoring IFN sensitivity in a subset of human bladder tumors.
authors.affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Papageorgiou
authors.forename: Laura
authors.initials: L
authors.lastname: Lashinger
authors.forename: Randall
authors.initials: R
authors.lastname: Millikan
authors.forename: H Barton
authors.initials: HB
authors.lastname: Grossman
authors.forename: William
authors.initials: W
authors.lastname: Benedict
authors.forename: Colin P N
authors.initials: CP
authors.lastname: Dinney
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology*; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D011719:Pyrazines / Q000494:pharmacology; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; D061945:Caspase Inhibitors; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D011719:Pyrazines; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases