ATG5 mediates a positive feedback loop between wnt signaling and autophagy in melanoma

Abibatou Ndoye, Anna Budina-Kolomets, Curtis H. Kugel, Marie R. Webster, Amanpreet Kaur, Reeti Behera, Vito W. Rebecca, Ling Li, Patricia A. Brafford, Qin Liu, Y. N.Vashisht Gopal, Michael A. Davies, Gordon Mills, Xiaowei Xu, Hong Wu, Meenhard Herlyn, Michael C. Nicastri, Jeffrey D. Winkle, Maria S. Soengas, Ravi K. AmaravadiMaureen E. Murphy, Ashani T. Weeraratna

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-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 β-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 β-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. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing β-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account.

Original languageEnglish (US)
Pages (from-to)5873-5885
Number of pages13
JournalCancer Research
Volume77
Issue number21
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ndoye, A., Budina-Kolomets, A., Kugel, C. H., Webster, M. R., Kaur, A., Behera, R., Rebecca, V. W., Li, L., Brafford, P. A., Liu, Q., Gopal, Y. N. V., Davies, M. A., Mills, G., Xu, X., Wu, H., Herlyn, M., Nicastri, M. C., Winkle, J. D., Soengas, M. S., ... Weeraratna, A. T. (2017). ATG5 mediates a positive feedback loop between wnt signaling and autophagy in melanoma. Cancer Research, 77(21), 5873-5885. https://doi.org/10.1158/0008-5472.CAN-17-0907