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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 FZD(8) 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 p...

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Autores principales: Murillo-Garzón, Virginia, Gorroño-Etxebarria, Irantzu, Åkerfelt, Malin, Puustinen, Mikael Christer, Sistonen, Lea, Nees, Matthias, Carton, James, Waxman, Jonathan, Kypta, Robert M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931552/
https://www.ncbi.nlm.nih.gov/pubmed/29717114
http://dx.doi.org/10.1038/s41467-018-04042-w
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author Murillo-Garzón, Virginia
Gorroño-Etxebarria, Irantzu
Åkerfelt, Malin
Puustinen, Mikael Christer
Sistonen, Lea
Nees, Matthias
Carton, James
Waxman, Jonathan
Kypta, Robert M.
author_facet Murillo-Garzón, Virginia
Gorroño-Etxebarria, Irantzu
Åkerfelt, Malin
Puustinen, Mikael Christer
Sistonen, Lea
Nees, Matthias
Carton, James
Waxman, Jonathan
Kypta, Robert M.
author_sort Murillo-Garzón, Virginia
collection PubMed
description Wnt-11 promotes cancer cell migration and invasion independently of β-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-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 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. 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, FZD(8) forms a TGF-β-regulated complex with TGF-β 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-β signals in prostate cancer.
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spelling pubmed-59315522018-05-07 Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer Murillo-Garzón, Virginia Gorroño-Etxebarria, Irantzu Åkerfelt, Malin Puustinen, Mikael Christer Sistonen, Lea Nees, Matthias Carton, James Waxman, Jonathan Kypta, Robert M. Nat Commun Article Wnt-11 promotes cancer cell migration and invasion independently of β-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-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 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. 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, FZD(8) forms a TGF-β-regulated complex with TGF-β 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-β signals in prostate cancer. Nature Publishing Group UK 2018-05-01 /pmc/articles/PMC5931552/ /pubmed/29717114 http://dx.doi.org/10.1038/s41467-018-04042-w Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Murillo-Garzón, Virginia
Gorroño-Etxebarria, Irantzu
Åkerfelt, Malin
Puustinen, Mikael Christer
Sistonen, Lea
Nees, Matthias
Carton, James
Waxman, Jonathan
Kypta, Robert M.
Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer
title Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer
title_full Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer
title_fullStr Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer
title_full_unstemmed Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer
title_short Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer
title_sort frizzled-8 integrates wnt-11 and transforming growth factor-β signaling in prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931552/
https://www.ncbi.nlm.nih.gov/pubmed/29717114
http://dx.doi.org/10.1038/s41467-018-04042-w
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