Frizzled-8 Integrates Wnt-11 and Transforming Growth factor-β Signaling in Prostate Cancer

Nat Commun. 2018 May 1;9(1):1747. doi: 10.1038/s41467-018-04042-w.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2 / metabolism
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Gene Silencing
  • Humans
  • Male
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Wnt Proteins / metabolism*

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Fzd8 protein, human
  • Receptors, Cell Surface
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Transforming Growth Factor beta
  • Wnt Proteins
  • Wnt11 protein, human