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

Virginia Murillo-Garzón; Irantzu Gorroño-Etxebarria; Malin Åkerfelt; Mikael Christer Puustinen; Lea Sistonen; Matthias Nees; James Carton; Jonathan Waxman; Robert M Kypta

doi:10.1038/s41467-018-04042-w

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

Virginia Murillo-Garzón, Irantzu Gorroño-Etxebarria, Malin Åkerfelt, Mikael Christer Puustinen, Lea Sistonen, Matthias Nees, James Carton, Jonathan Waxman, Robert M Kypta

Biochemistry and Cell Biology

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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.

Original language	English
Pages (from-to)	1-16
Number of pages	16
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04042-w
Publication status	Published - 1 May 2018
MoE publication type	A1 Journal article-refereed

Keywords

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

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Murillo-Garzon et al 2018 (1).pdfFinal published version, 3.2 MBLicence: Publisher rights policy

http://urn.fi/URN:NBN:fi-fe2020100883423

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title = "Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer",

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.",

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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

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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.

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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

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JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

Keywords

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