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. and Kypta, R.M. 2009. Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer. British Journal of Cancer. 100, pp. 1165-1174. https://doi.org/10.1038/sj.bjc.6604976

TitleSecreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer
TypeJournal article
AuthorsKawano, Y., Diez, S., Uysal-Onganer, P., Darrington, R.S., Waxman, J. and Kypta, R.M.
Abstract

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/Ca2+ 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.

JournalBritish Journal of Cancer
Journal citation100, pp. 1165-1174
ISSN1532-1827
0007-0920
Year2009
PublisherNature Publishing Group
Digital Object Identifier (DOI)https://doi.org/10.1038/sj.bjc.6604976
Publication dates
Published10 Mar 2009
ISBN00070920 15321827

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