Abstract
While the TRAIL pathway represents a promising therapeutic target in melanoma, resistance to TRAIL-mediated apoptosis remains a barrier to its successful adoption. Since the Wnt/β-catenin pathway has been implicated in facilitating melanoma cell apoptosis, we investigated the effect of Wnt/β-catenin signaling on regulating the responses of melanoma cells to TRAIL. Co-treatment of melanoma cell lines with WNT3A-conditioned media and recombinant TRAIL significantly enhanced apoptosis compared to treatment with TRAIL alone. This apoptosis correlates with increased abundance of the pro-apoptotic proteins BCL2L11 and BBC3, and with decreased abundance of the anti-apoptotic regulator Mcl1. We then confirmed the involvement of the Wnt/β-catenin signaling pathway by demonstrating that siRNA-mediated knockdown of an intracellular β-catenin antagonist, AXIN1, or treating cells with an inhibitor of GSK-3 also enhanced melanoma cell sensitivity to TRAIL. These studies describe a novel regulation of TRAIL sensitivity in melanoma by Wnt/β-catenin signaling, and suggest that strategies to enhance Wnt/β-catenin signaling in combination with TRAIL agonists warrant further investigation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis*
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Axin Protein / antagonists & inhibitors
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Bcl-2-Like Protein 11
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Cell Culture Techniques
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Cell Line, Tumor
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Culture Media, Conditioned
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Humans
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Melanoma / metabolism*
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Melanoma / pathology
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Membrane Proteins / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins / metabolism
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RNA Interference
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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Wnt Signaling Pathway*
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Wnt3A Protein / pharmacology*
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beta Catenin / metabolism*
Substances
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AXIN1 protein, human
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Apoptosis Regulatory Proteins
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Axin Protein
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BBC3 protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Culture Media, Conditioned
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MCL1 protein, human
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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WNT3A protein, human
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Wnt3A Protein
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beta Catenin
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Glycogen Synthase Kinase 3