Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer.

Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD₈ is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD₈ in cancer, correlating with Wnt-11. FZD₈ co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD₈ forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD₈ and TGFBR1. Targeting FZD₈ may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer.

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