title: Activation of Wnt/β-catenin signaling increases apoptosis in melanoma cells treated with trail.
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.
authors.affiliation: Department of Medicine, the University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Zachary F
authors.initials: ZF
authors.lastname: Zimmerman
authors.forename: Rima M
authors.initials: RM
authors.lastname: Kulikauskas
authors.forename: Karol
authors.initials: K
authors.lastname: Bomsztyk
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Chien
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D060466:Axin Protein / Q000037:antagonists & inhibitors; D000072224:Bcl-2-Like Protein 11; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C555451:AXIN1 protein, human; D051017:Apoptosis Regulatory Proteins; D060466:Axin Protein; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D017077:Culture Media, Conditioned; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3