Wnt-11 promotes neuroendocrine-like differentiation, cell survival and migration in advanced prostate cancer


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Pinar Uysal-Onganer1, Soraya Diez1, Yoshiaki Kawano1, Siobhan Darrington1, Marjorie Walker1, Jonathan Waxman1, Robert Kypta2

1Imperial College London, London, UK, 2Centre for Cooperative Research in Biosciences, Bilbao, Spain

Abstract

We previously reported that androgens repress Wnt-11 expression in androgen-dependent prostate cancer cells and that Wnt-11 represses AR transcriptional activity. This mutual repression is lost in castration-resistant prostate cancer, where Wnt-11 mRNA expression is frequently upregulated (Zhu et al., Cancer Research, 2004). Prostate tumour tissue arrays have now been used to analyse Wnt-11 protein expression levels. Wnt11 was detected at low levels in normal prostate epithelial cells, was upregulated in two thirds of prostate tumours, and was also found in prostate tumour metastases. The role of Wnt11 in prostate cancer was further investigated using gene silencing and overexpression. Androgen depletion of LNCaP cells normally leads to cell cycle arrest and neuroendocrine (NE)-like differentiation. Prevention of Wnt11 upregulation in androgen-depleted LNCaP cells by gene silencing reduced NE-like differentiation and increased apoptosis in hormone-depleted prostate cancer cells. Moreover, ectopic expression of Wnt11 in LNCaP cells increased expression of NE genes and reduced cell proliferation. Additional studies using PC3 cells support a role for Wnt11 in survival, NE-like differentiation and migration of castration resistant prostate cancer cells. NE-like differentiation is frequently observed in prostate cancer metastases and the number of NE-like cells correlates negatively with patient survival, particularly in recurrent prostate cancer. Our observations suggest that Wnt11 could be a useful therapeutic target for recurrent prostate cancer.

We previously reported that androgens repress Wnt-11 expression in androgen-dependent prostate cancer cells and that Wnt-11 represses AR transcriptional activity. This mutual repression is lost in castration-resistant prostate cancer, where Wnt-11 mRNA expression is frequently upregulated (Zhu et al., Cancer Research, 2004). Prostate tumour tissue arrays have now been used to analyse Wnt-11 protein expression levels. Wnt11 was detected at low levels in normal prostate epithelial cells, was upregulated in two thirds of prostate tumours, and was also found in prostate tumour metastases. The role of Wnt11 in prostate cancer was further investigated using gene silencing and overexpression. Androgen depletion of LNCaP cells normally leads to cell cycle arrest and neuroendocrine (NE)-like differentiation. Prevention of Wnt11 upregulation in androgen-depleted LNCaP cells by gene silencing reduced NE-like differentiation and increased apoptosis in hormone-depleted prostate cancer cells. Moreover, ectopic expression of Wnt11 in LNCaP cells increased expression of NE genes and reduced cell proliferation. Additional studies using PC3 cells support a role for Wnt11 in survival, NE-like differentiation and migration of castration resistant prostate cancer cells. NE-like differentiation is frequently observed in prostate cancer metastases and the number of NE-like cells correlates negatively with patient survival, particularly in recurrent prostate cancer. Our observations suggest that Wnt11 could be a useful therapeutic target for recurrent prostate cancer.

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