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


RESULTS
Wnt-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.


CONCLUSIONS
These 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.
Uysal-Onganer
Pinar
P
Department of Oncology, Imperial College London, London, UK. p.onganer@imperial.ac.uk
Kawano
Yoshiaki
Y
Caro
Mercedes
M
Walker
Marjorie M
MM
Diez
Soraya
S
Darrington
R Siobhan
RS
Waxman
Jonathan
J
Kypta
Robert M
RM
D000728:Androgens / Q000172:deficiency / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D055099:Neuroendocrine Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D000728:Androgens; D051153:Wnt Proteins; C540523:Wnt11 protein, human