title: Tumor necrosis factor-related apoptosis-inducing ligand can induce apoptosis in subsets of premalignant cells.
abstract: During the transformation from a normal to a malignant cell, several mutations are required to bypass the pathways responsible for controlling proliferation. Premalignant cells have acquired some, but not all of these mutations and consequently have not yet attained a malignant phenotype characterized by tumor formation in vivo. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in malignant cells while sparing normal ones and is currently being considered as adjuvant therapy for various human malignancies. Whether TRAIL is effective in inducing apoptosis in premalignant cells is unclear, however. We studied the effect of TRAIL on two human premalignant cell lines the SV7tert and HA1E cells. Both cell lines had been immortalized by the addition of simian virus 40 large T antigen and the telomerase subunit hTERT, but had not been transformed into malignant cells. TRAIL initiated apoptosis by activating both the mitochondrial-independent and -dependent apoptotic pathways in both cell lines at relatively low doses whereas it had no effect on normal human pulmonary artery smooth muscle cells even at high doses. These results suggest that TRAIL can induce apoptosis in premalignant cells and suggests a novel therapy for the treatment of premalignant lesions in vivo.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Lu
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.forename: James
authors.initials: J
authors.lastname: West
authors.forename: Marloes
authors.initials: M
authors.lastname: Hoedt-Miller
authors.forename: Alison
authors.initials: A
authors.lastname: Sheridan
authors.forename: Baskaran
authors.initials: B
authors.lastname: Govindarajan
authors.forename: Julie Wright
authors.initials: JW
authors.lastname: Harral
authors.forename: David M
authors.initials: DM
authors.lastname: Rodman
authors.forename: Brian
authors.initials: B
authors.lastname: Fouty
mesh_terms: D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000473:pathology; D010641:Phenotype; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D019098:Telomerase / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D019098:Telomerase; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases