Abstract
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.
Highlights
Wnt-11 is a secreted protein that modulates cell growth, differentiation and morphogenesis during development
The morphology of Wnt-11-transfected LNCaP cells resembles that of androgen-depleted LNCaP cells as they undergo neuroendocrine-like differentiation (NED) [12], which we previously reported induces expression of endogenous Wnt-11 [2]
Increased expression of Wnt-11 in prostate tumours In order to determine whether Wnt-11 protein levels are elevated in patient tumours, we used anti-Wnt-11 antibodies to localise Wnt-11 expression in sections taken from human prostate and prostate tumour tissue (Figure 1)
Summary
Wnt-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. The prevalence of increased expression of Wnt-11 in patient tumours and the functions of Wnt-11 in prostate cancer cells were not known. We have previously reported increased expression of Wnt-11 mRNA in androgen-independent prostate cancer (PCa) [2]. Wnt-11 has been reported to inhibit JNK and NF-kappaB [8], activate PKC and JNK [9] and activate cAMP response element binding protein (CREB) family members [10]. Wnt-11 does not appear to stabilise b-catenin and is frequently found to inhibit ‘canonical’ Wnt/b-catenin signalling [2,8,11]
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