An Autocrine Wnt5a Loop Promotes NF-κB Pathway Activation and Cytokine/Chemokine Secretion in Melanoma

Abstract

Wnt5a signaling has been implicated in the progression of cancer by regulating multiple cellular processes, largely migration and invasion, epithelial-mesenchymal transition (EMT), and metastasis. Since Wnt5a signaling has also been involved in inflammatory processes in infectious and inflammatory diseases, we addressed the role of Wnt5a in regulating NF-κB, a pivotal mediator of inflammatory responses, in the context of cancer. The treatment of melanoma cells with Wnt5a induced phosphorylation of the NF-κB subunit p65 as well as IKK phosphorylation and IκB degradation. By using cDNA overexpression, RNA interference, and dominant negative mutants we determined that ROR1, Dvl2, and Akt (from the Wnt5a pathway) and TRAF2 and RIP (from the NF-κB pathway) are required for the Wnt5a/NF-κB crosstalk. Wnt5a also induced p65 nuclear translocation and increased NF-κB activity as evidenced by reporter assays and a NF-κB-specific upregulation of RelB, Bcl-2, and Cyclin D1. Further, stimulation of melanoma cells with Wnt5a increased the secretion of cytokines and chemokines, including IL-6, IL-8, IL-11, and IL-6 soluble receptor, MCP-1, and TNF soluble receptor I. The inhibition of endogenous Wnt5a demonstrated that an autocrine Wnt5a loop is a major regulator of the NF-κB pathway in melanoma. Taken together, these results indicate that Wnt5a activates the NF-κB pathway and has an immunomodulatory effect on melanoma through the secretion of cytokines and chemokines.

Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma—An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer

“…Using the tumor marker model depicted by Figure 2, this decrease of S100B might be explained by a yet not understood effect of PD-1 blockade on melanoma cell cycle resulting in partial cell cycle arrest and reduced S100B release. It has been observed that melanoma cells may rely on an autocrine secretion of IL-6 [36]. The parallel decrease of IL-6 might indicate that PD-1 blockade interferes with this autocrine IL-6 loop.…”

“…Nevertheless, two patients in our study demonstrated an immediate and parallel decrease of IL-6 and S100B serum levels after administration of checkpoint inhibitor treatment which might result from a direct suppressive effect of PD-1 blockade on melanoma cell cycle. Under the assumption that IL-6 can be excreted by melanoma cells and may stimulate autocrine growth [36], the parallel decrease of IL-6 in these patients might suggest that blockade of PD-1 did interrupt this putative autocrine loop. High levels of IL-6 secreted by melanoma metastases might mask the IL-6 protein signature deriving from immune activation.…”

BCL2L10 Is Overexpressed in Melanoma Downstream of STAT3 and Promotes Cisplatin and ABT-737 Resistance

“…Silencing of BCL2L10 was performed using pLKO.1 shRNA clones TRCN0000033595 and TRCN0000033596 designed by The RNAi Consortium (TRC) and previously validated [ 84 ]. Viral particles were generated as described [ 85 ].…”

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

“…IL6ST (Interleukin-6 receptor subunit beta) is involved in transducing multiple signals, such as IL-6 and IL-11, and might be crucial in severe COVID-19 cases90 . ROR1 (Inactive tyrosine-protein kinase transmembrane receptor ROR1) acts as a receptor, and when activated by WNT5A ligand binding, activates NFB signaling91 . Finally, PTPRJ (Receptor-type tyrosine-protein phosphatase eta; CD148) regulates endothelial cell survival, enhancing epithelial cell junctions as well as VEGF-induced SRC and AKT activation 92 .…”