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Ndoye A, Budina-Kolomets A, Kugel CH, Webster MR, Kaur A, Behera R, Rebecca VW, Li L, Brafford PA, Liu Q, Gopal YN, Davies MA, Mills GB, Xu X, Wu H, Herlyn M, Nicastri MC, Winkler JD, Soengas MS, Amaravadi RK, Murphy ME, Weeraratna AT
ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma
Cancer Res (2017) 77:5873-5885.
Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of beta-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low beta-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5A(high) cells decreased Wnt5A and increased beta-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5A(high) cells were less sensitive to Lys05 and could be reverted by inducing beta-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. Cancer Res; 77(21); 5873-85. (c)2017 AACR.
Publication Date: 2017-11-01.
PMCID: PMC5718045
Last updated on Monday, May 04, 2020