TY - JOUR
T1 - Frizzled-8 integrates Wnt-11 and transforminggrowth factor-βsignaling in prostate cancer
AU - Murillo-Garzón, Virginia
AU - Gorroño-Etxebarria, Irantzu
AU - Åkerfelt, Malin
AU - Puustinen, Mikael
AU - Sistonen, Lea
AU - Nees, Matthias
AU - Carton, James
AU - Waxman, Jonathan
AU - Kypta, Robert M.
PY - 2018
Y1 - 2018
N2 - Wnt-11 promotes cancer cell migration and invasion independently of beta-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD(8) is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-beta signals to promote EMT. FZD(8) 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 FZD(8) in cancer, correlating with Wnt-11. FZD(8) co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD(8) silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-beta/Smad-dependent signaling. Mechanistically, FZD(8) forms a TGF-beta-regulated complex with TGF-beta receptors that is mediated by the extracellular domains of FZD(8) and TGFBR1. Targeting FZD(8) may therefore inhibit aberrant activation of both Wnt and TGF-beta signals in prostate cancer.
AB - Wnt-11 promotes cancer cell migration and invasion independently of beta-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD(8) is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-beta signals to promote EMT. FZD(8) 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 FZD(8) in cancer, correlating with Wnt-11. FZD(8) co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD(8) silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-beta/Smad-dependent signaling. Mechanistically, FZD(8) forms a TGF-beta-regulated complex with TGF-beta receptors that is mediated by the extracellular domains of FZD(8) and TGFBR1. Targeting FZD(8) may therefore inhibit aberrant activation of both Wnt and TGF-beta signals in prostate cancer.
U2 - 10.1038/s41467-018-04042-w
DO - 10.1038/s41467-018-04042-w
M3 - Artikel
SN - 2041-1723
VL - 9
SP - –
JO - Nature Communications
JF - Nature Communications
ER -