TRAIL is a promising therapeutic agent for human malignancies. TRAIL often requires mitochondrial dysfunction, referred to as the Type II death receptor pathway, to promote cytotoxicity. However, numerous malignant cells are TRAIL resistant due to inhibition of this mitochondrial pathway. Using cholangiocarcinoma cells as a model of TRAIL resistance, we found that Hedgehog signaling blockade sensitized these cancer cells to TRAIL cytotoxicity independent of mitochondrial dysfunction, referred to as Type I death receptor signaling. This switch in TRAIL requirement from Type II to Type I death receptor signaling was demonstrated by the lack of functional dependence on Bid/Bim and Bax/Bak, proapoptotic components of the mitochondrial pathway. Hedgehog signaling modulated expression of X-linked inhibitor of apoptosis (XIAP), which serves to repress the Type I death receptor pathway. siRNA targeted knockdown of XIAP mimics sensitization to mitochondria-independent TRAIL killing achieved by Hedgehog inhibition. Regulation of XIAP expression by Hedgehog signaling is mediated by the glioma-associated oncogene 2 (GLI2), a downstream transcription factor of Hedgehog. In conclusion, these data provide additional mechanisms modulating cell death by TRAIL and suggest Hedgehog inhibition as a therapeutic approach for TRAIL-resistant neoplasms.
Apoptosis, Apoptosis Regulatory Proteins, BH3 Interacting Domain Death Agonist Protein, Cell Line, Cell Line, Tumor, Chromatin Immunoprecipitation, Electrophoretic Mobility Shift Assay, Hedgehog Proteins, Humans, Immunoblotting, Inhibitor of Apoptosis Proteins, Kruppel-Like Transcription Factors, Membrane Proteins, Nuclear Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, Transcription Factors, Veratrum Alkaloids, X-Linked Inhibitor of Apoptosis Protein, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
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