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Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer

Secreted Frizzled-related protein-1 (sFRP1) associates with Wnt proteins and its loss can lead to activation of Wnt/β-catenin signalling. It is frequently downregulated in cancer, including prostate cancer, but its function in prostate cancer is unclear because it can increase proliferation of prost...

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Autores principales: Kawano, Y, Diez, S, Uysal-Onganer, P, Darrington, R S, Waxman, J, Kypta, R M
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669996/
https://www.ncbi.nlm.nih.gov/pubmed/19277043
http://dx.doi.org/10.1038/sj.bjc.6604976
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author Kawano, Y
Diez, S
Uysal-Onganer, P
Darrington, R S
Waxman, J
Kypta, R M
author_facet Kawano, Y
Diez, S
Uysal-Onganer, P
Darrington, R S
Waxman, J
Kypta, R M
author_sort Kawano, Y
collection PubMed
description Secreted Frizzled-related protein-1 (sFRP1) associates with Wnt proteins and its loss can lead to activation of Wnt/β-catenin signalling. It is frequently downregulated in cancer, including prostate cancer, but its function in prostate cancer is unclear because it can increase proliferation of prostate epithelial cells. We investigated the function of sFRP1 in androgen-dependent prostate cancer and found that sFRP1 inhibited androgen receptor (AR) transcriptional activity. In addition, sFRP1 inhibited the proliferation of androgen-dependent LNCaP cells but not of an androgen-independent subline LNCaP-r, suggesting a role in androgen-dependent growth. The inhibition of AR by sFRP1 was unaffected by co-expression of Wnt3a, stabilised β-catenin or β-catenin shRNA, suggesting it does not involve Wnt/β-catenin signalling. Wnt5a also inhibited AR and expression of Wnt5a and sFRP1 together did not further inhibit AR, suggesting that Wnt5a and sFRP1 activate the same signal(s) to inhibit AR. However, sFRP1 inhibition of AR was unaffected by inhibitors of kinases involved in Wnt/Ca(2+) and Wnt/planar cell polarity non-canonical Wnt signalling. Interestingly, the cysteine-rich domain of sFRP1 interacted with Frizzled receptors expressed in prostate cancer cells, suggesting that sFRP1/Frizzled complexes activate a signal that leads to repression of AR. Taken together, these observations highlight the function of β-catenin-independent Wnt signalling in the control of AR activity and provide one explanation for sFRP1 downregulation in prostate cancer.
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spelling pubmed-26699962010-04-07 Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer Kawano, Y Diez, S Uysal-Onganer, P Darrington, R S Waxman, J Kypta, R M Br J Cancer Molecular Diagnostics Secreted Frizzled-related protein-1 (sFRP1) associates with Wnt proteins and its loss can lead to activation of Wnt/β-catenin signalling. It is frequently downregulated in cancer, including prostate cancer, but its function in prostate cancer is unclear because it can increase proliferation of prostate epithelial cells. We investigated the function of sFRP1 in androgen-dependent prostate cancer and found that sFRP1 inhibited androgen receptor (AR) transcriptional activity. In addition, sFRP1 inhibited the proliferation of androgen-dependent LNCaP cells but not of an androgen-independent subline LNCaP-r, suggesting a role in androgen-dependent growth. The inhibition of AR by sFRP1 was unaffected by co-expression of Wnt3a, stabilised β-catenin or β-catenin shRNA, suggesting it does not involve Wnt/β-catenin signalling. Wnt5a also inhibited AR and expression of Wnt5a and sFRP1 together did not further inhibit AR, suggesting that Wnt5a and sFRP1 activate the same signal(s) to inhibit AR. However, sFRP1 inhibition of AR was unaffected by inhibitors of kinases involved in Wnt/Ca(2+) and Wnt/planar cell polarity non-canonical Wnt signalling. Interestingly, the cysteine-rich domain of sFRP1 interacted with Frizzled receptors expressed in prostate cancer cells, suggesting that sFRP1/Frizzled complexes activate a signal that leads to repression of AR. Taken together, these observations highlight the function of β-catenin-independent Wnt signalling in the control of AR activity and provide one explanation for sFRP1 downregulation in prostate cancer. Nature Publishing Group 2009-04-07 2009-03-10 /pmc/articles/PMC2669996/ /pubmed/19277043 http://dx.doi.org/10.1038/sj.bjc.6604976 Text en Copyright © 2009 Cancer Research UK https://creativecommons.org/licenses/by/4.0/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 https://creativecommons.org/licenses/by/4.0/.
spellingShingle Molecular Diagnostics
Kawano, Y
Diez, S
Uysal-Onganer, P
Darrington, R S
Waxman, J
Kypta, R M
Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer
title Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer
title_full Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer
title_fullStr Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer
title_full_unstemmed Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer
title_short Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer
title_sort secreted frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer
topic Molecular Diagnostics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669996/
https://www.ncbi.nlm.nih.gov/pubmed/19277043
http://dx.doi.org/10.1038/sj.bjc.6604976
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