TY - JOUR
T1 - ATG5 mediates a positive feedback loop between wnt signaling and autophagy in melanoma
AU - Ndoye, Abibatou
AU - Budina-Kolomets, Anna
AU - Kugel, Curtis H.
AU - Webster, Marie R.
AU - Kaur, Amanpreet
AU - Behera, Reeti
AU - Rebecca, Vito W.
AU - Li, Ling
AU - Brafford, Patricia A.
AU - Liu, Qin
AU - Gopal, Y. N.Vashisht
AU - Davies, Michael A.
AU - Mills, Gordon B.
AU - Xu, Xiaowei
AU - Wu, Hong
AU - Herlyn, Meenhard
AU - Nicastri, Michael C.
AU - Winkle, Jeffrey D.
AU - Soengas, Maria S.
AU - Amaravadi, Ravi K.
AU - Murphy, Maureen E.
AU - Weeraratna, Ashani T.
N1 - Funding Information:
A.T. Weeraratna, A. Kaur, and R. Behera are supported by R01CA174746. A. Ndoye, A. Budina-Kolomets, V.W. Rebecca, M. Murphy, R. Amaravadi, and A.T. Weeraratna are supported by P01 CA114046 and A. Ndoye, A.T. Weeraratna, and R. Amaravadi are also supported by P50CA174523. C.H. Kugel III is supported by T32CA009171. M.R. Webster is supported by K99 CA208012-01. R. Amaravadi is supported by R01CA169134M. Soengas and A.T. Weerar-atna are also supported by a Melanoma Research Alliance/L'Oréal Paris-USA Women in Science Team Science Award. A. Budina-Kolomets and M.E. Murphy are supported by R01 CA139319. M. Herlyn and G.B. Mills are supported by a gift from the Adelson Medical Research Foundation. Core facilities used in this grant are supported by P30CA010815 and NCI#CA16672.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-0907
DO - 10.1158/0008-5472.CAN-17-0907
M3 - Article
C2 - 28887323
AN - SCOPUS:85035070849
SN - 0008-5472
VL - 77
SP - 5873
EP - 5885
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -