Autophagy promotes tumor survival and resistance to various anticancer drugs. In melanoma, we have previously shown that non-canonical Wnt signaling, which is mediated by Wnt5A, promotes melanoma invasion and drug resistance. The Wnt5A-mediated degradation of β-catenin also promotes melanoma metastasis. Previous studies have shown that in advanced stages of malignancy, melanoma tumors upregulate autophagy in order to alleviate metabolic and drug induced stress in the tumor microenvironment. Although preclinical studies and clinical trials show a potential for autophagy as a target for melanoma, there is a still a great need to understand the mechanisms by which melanoma tumors upregulate autophagy. In this study, we investigate how the Wnt signaling of melanoma tumors affect autophagy and pharmacological-mediated autophagy inhibition by combining expression and histochemical analysis of melanoma human patient biopsies with analysis in melanoma cells lines and mouse models. Our data show that high Wnt5A and low β-catenin in melanoma correlates with high autophagy. By genetic overexpression of Wnt5A or treatment with recombinant Wnt5A, we also observed an increase in autophagy in many melanoma cell lines. Conversely, the inhibition of autophagy by shRNA mediated knockdown of the major autophagy gene, ATG5 leads to a decrease in Wnt5A and an increase in β-catenin. This switch from non-canonical Wnt signaling to canonical Wnt signaling also led to a decrease in melanoma cell invasion. To define the relevance of this feedback loop between Wnt signaling and autophagy, we tested whether the Wnt signature of melanoma tumors would affect response to autophagy inhibition and found that both in vitro and in vivo Wnt5A decreased the sensitivity of melanoma cells to the lysosomal autophagy inhibitor lys05. Increasing β-catenin in malignant Wnt5A-high (β-catenin –low) melanoma tumors by either genetic stabilization of β-catenin or by treatment with β-catenin activators increased the response to autophagy inhibition. Overall our data show that there is a feedback loop between Wnt signaling and autophagy in melanoma which affects response to autophagy inhibition. Modulation of Wnt signaling in aggressive melanoma could improve autophagy inhibition in melanoma tumors.
|School:||University of the Sciences in Philadelphia|
|Department:||Arts and Sciences|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 79/12(E), Dissertation Abstracts International|
|Subjects:||Biology, Molecular biology, Oncology|
|Keywords:||Aging, Autophagy, Cancer, Melanoma, Tumor microenvironment, Wnt signaling|
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