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

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 physiological 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.

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti–PD-1 immunotherapy

“…Notably, the release of HSP70 was not found to be due simply to a cell death-dependent mechanism, as dacarbazine chemotherapy readily induced tumor apoptosis in the BRAF V600E melanoma model but did not induce significant levels of HSP70 release. Although HSP70 has been identified within tumor-derived exosomes, prior studies have also suggested that soluble HSP70 may be released 18,38,39). However, a mechanistic description of how Wnt5a promotes immune tolerance and immunotherapy resistance remains incomplete.…”

WNT Signaling in Melanoma

“…Furthermore, it has been reported that WNT5A increases autophagy, which mediates resistance to various anticancer drugs. Knocking down autophagy-related gene 5 (ATG5) in WNT5A high melanoma cells caused a reduction of the WNT5A level and induction of β-catenin [ 130 ].…”

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

“…Certain regulators relevant for melanoma can inhibit autophagy as shown for neural cell adhesion molecule (NCAM) [97], minichromosome maintenance protein 7 (MCM7) [98] and Wingless-type (WNT)/β-catenin cascade [99]. In line with this, high level of WNT5a, which regulates the activity of non-canonical WNT signaling pathway, and low level of β-catenin were associated with increased basal autophagy in melanoma cells [100]. In turn, downregulation of ATG5 in WNT5a high melanoma cells was associated with lower level of WNT5a and increased level of β-catenin [100], supporting the conclusion that autophagy is inversely correlated with the activity of canonical WNT/β-catenin signaling pathway.…”