ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma

作者：Ndoye Abibatou; Budina Kolomets Anna; Kugel Curtis H III; Webster Marie R; Kaur Amanpreet; Behera Reeti; Rebecca Vito W; Li Ling; Brafford Patricia A; Liu Qin; Gopal Y N Vashisht; Davies Michael A; Mills Gordon B; Xu Xiaowei; Wu Hong; Herlyn Meenhard; Nicastri Michael C; Winkler Jeffrey D; Soengas Maria S; Amaravadi Ravi K; Murphy Maureen E; Weeraratna Ashani T^*

来源：Cancer Research, 2017, 77(21): 5873-5885.

DOI：10.1158/0008-5472.CAN-17-0907

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 Wnt5Ahigh 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.

• 出版日期2017-11-1