title: TRAIL mediates apoptosis in cancerous but not normal primary cultured cells of the human reproductive tract.
abstract: Cancer of the reproductive tract encompasses malignancies of the uterine corpus, cervix, ovary, Fallopian tube, among others and accounts for 15% of female cancer mortalities. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates apoptosis by binding to death receptors and offers a promising cancer treatment. The goal of this study was to investigate and characterize the effect of TRAIL in endometrial cancer cell lines and normal (non-cancerous) epithelial cells of endometrial origin. We also examined the effect of TRAIL in other primary cultured cancers and normal cells of the human female reproductive tract and evaluated if TRAIL mediated apoptosis correlated with death receptors and decoy receptors 1 and 2.Herein, we demonstrate that TRAIL at concentrations which kill cancerous cells, does not mediate apoptosis or alter cell viability in normal human endometrium, ovary, cervix or Fallopian tube. The partial inhibition by a caspase 9 inhibitor and the total inhibition by a caspase 8 inhibitor demonstrates the dependency on the extrinsic apoptotic pathway. The selective mortality does not correlate with the presence of death or decoy receptors. These results suggest that TRAIL may be an effective treatment for endometrial cancer and other female reproductive cancers, with minimal secondary effects on healthy tissue.
authors.affiliation: Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile.
authors.forename: Anil
authors.initials: A
authors.lastname: Sadarangani
authors.forename: Sumie
authors.initials: S
authors.lastname: Kato
authors.forename: Natalia
authors.initials: N
authors.lastname: Espinoza
authors.forename: Soledad
authors.initials: S
authors.lastname: Lange
authors.forename: Carmen
authors.initials: C
authors.lastname: Llados
authors.forename: Marisol
authors.initials: M
authors.lastname: Espinosa
authors.forename: Manuel
authors.initials: M
authors.lastname: Villalón
authors.forename: Stanley
authors.initials: S
authors.lastname: Lipkowitz
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cuello
authors.forename: Gareth I
authors.initials: GI
authors.lastname: Owen
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D005836:Genitalia, Female / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D018076:DNA, Complementary; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human