期刊
PLOS ONE
卷 8, 期 7, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0069593
关键词
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资金
- Bridge Funding through the University of Washington Provost's Office
- National Institutes of Health
- National Institutes of Health [T32-CA009515, R37-DK45978, R01-DK083310]
- University of Washington's Office of the Provost
- University Of Washington Division Of Dermatology
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/beta-catenin pathway has been implicated in facilitating melanoma cell apoptosis, we investigated the effect of Wnt/beta-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/beta-catenin signaling pathway by demonstrating that siRNA-mediated knockdown of an intracellular beta-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/beta-catenin signaling, and suggest that strategies to enhance Wnt/beta-catenin signaling in combination with TRAIL agonists warrant further investigation.
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