Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells

Molecular Cancer

Research

Mercedes Caro¹  Marjorie M Walker²  Soraya Diez³  Jonathan Waxman³  Pinar Uysal-Onganer³  Yoshiaki Kawano³  R Siobhan Darrington³  Robert M Kypta⁴ 

[1] Centre for Cooperative Research in Biosciences (CIC bioGUNE), Derio, Spain;Department of Histopathology, Imperial College London, London, UK;Department of Oncology, Imperial College London, London, UK;Department of Oncology, Imperial College London, London, UK;Centre for Cooperative Research in Biosciences (CIC bioGUNE), Derio, Spain;

关键词: Androgen Receptor;    Prostate Cancer Cell;    LNCaP Cell;    cAMP Response Element Binding;    Androgen Receptor Expression;   

DOI  :  10.1186/1476-4598-9-55

 received in 2009-11-19, accepted in 2010-03-10,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundWnt-11 is a secreted protein that modulates cell growth, differentiation and morphogenesis during development. We previously reported that Wnt-11 expression is elevated in hormone-independent prostate cancer and that the progression of prostate cancer from androgen-dependent to androgen-independent proliferation correlates with a loss of mutual inhibition between Wnt-11- and androgen receptor-dependent signals. However, the prevalence of increased expression of Wnt-11 in patient tumours and the functions of Wnt-11 in prostate cancer cells were not known.ResultsWnt-11 protein levels in prostate tumours were determined by immunohistochemical analysis of prostate tumour tissue arrays. Wnt-11 protein was elevated in 77/117 of tumours when compared with 27 benign prostatic hypertrophy specimens and was present in 4/4 bone metastases. In addition, there was a positive correlation between Wnt-11 expression and PSA levels above 10 ng/ml. Androgen-depleted LNCaP prostate cancer cells form neurites and express genes associated with neuroendocrine-like differentiation (NED), a feature of prostate tumours that have a poor prognosis. Since androgen-depletion increases expression of Wnt-11, we examined the role of Wnt-11 in NED. Ectopic expression of Wnt-11 induced expression of NSE and ASCL1, which are markers of NED, and this was prevented by inhibitors of cyclic AMP-dependent protein kinase, consistent with the known role of this kinase in NED. In contrast, Wnt-11 did not induce NSE expression in RWPE-1 cells, which are derived from benign prostate, suggesting that the role of Wnt-11 in NED is specific to prostate cancer. In addition, silencing of Wnt-11 expression in androgen-depleted LNCaP cells prevented NED and resulted in apoptosis. Silencing of Wnt-11 gene expression in androgen-independent PC3 cells also reduced expression of NSE and increased apoptosis. Finally, silencing of Wnt-11 reduced PC3 cell migration and ectopic expression of Wnt-11 promoted LNCaP cell invasion.ConclusionsThese observations suggest that the increased level of Wnt-11 found in prostate cancer contributes to tumour progression by promoting NED, tumour cell survival and cell migration/invasion, and may provide an opportunity for novel therapy in prostate cancer.

【 授权许可】

CC BY   
© Uysal-Onganer et al; licensee BioMed Central Ltd. 2010