TY - JOUR
T1 - Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer
AU - Murillo-Garzón, Virginia
AU - Gorroño-Etxebarria, Irantzu
AU - Åkerfelt, Malin
AU - Puustinen, Mikael Christer
AU - Sistonen, Lea
AU - Nees, Matthias
AU - Carton, James
AU - Waxman, Jonathan
AU - Kypta, Robert M
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
KW - Activating Transcription Factor 2/metabolism
KW - Cell Line, Tumor
KW - Epithelial-Mesenchymal Transition
KW - Gene Silencing
KW - Humans
KW - Male
KW - Neoplasm Invasiveness
KW - Neoplasm Metastasis
KW - Prostatic Neoplasms/metabolism
KW - Receptors, Cell Surface/genetics
KW - Receptors, Transforming Growth Factor beta/metabolism
KW - Signal Transduction
KW - Smad Proteins/metabolism
KW - Transforming Growth Factor beta/metabolism
KW - Wnt Proteins/metabolism
U2 - 10.1038/s41467-018-04042-w
DO - 10.1038/s41467-018-04042-w
M3 - Article
C2 - 29717114
SN - 2041-1723
VL - 9
SP - 1
EP - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -