title: X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells.
abstract: Although the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to play an important role in the immunosurveillance of neoplasia, apoptotic factors that modulate the sensitivity of cancer cells to TRAIL are poorly understood. The inhibitor of apoptosis proteins (IAPs) have generated considerable interest as potential targets for cancer therapy, but the lack of a phenotype in X-linked IAP (XIAP) knockout mice has generated speculation that IAP function may be redundant. Using gene targeting technology, we show that disruption of the gene encoding XIAP in human cancer cells did not interfere with basal proliferation, but caused a remarkable sensitivity to TRAIL. These results demonstrate that XIAP is a nonredundant modulator of TRAIL-mediated apoptosis and provide a rationale for XIAP as a therapeutic target.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Cummins
authors.forename: Manu
authors.initials: M
authors.lastname: Kohli
authors.forename: Carlo
authors.initials: C
authors.lastname: Rago
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Fred
authors.initials: F
authors.lastname: Bunz
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003110:Colonic Neoplasms / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases