Wnt Signalling in Prostate Cancer

 

The Wnt signalling pathway is aberrantly activated in many tumours, including those of the prostate, where beta-catenin accumulates in cell nuclei and can act as a transcriptional co-regulator for both Tcf/LEF family members and the androgen receptor (AR).  In contrast to the situation in colon cancer, mutations that stabilise beta-catenin are rare in prostate cancer. In order to determine the mechanism of beta-catenin activation, we have characterised components of the Wnt pathway in normal prostate and prostate cancer cells.

Wnt ligands

The expression level of several Wnt ligands was found to be altered in advanced prostate cancer cells (Zhu et al., 2004). One of these is Wnt-11, a so-called ‘noncanonical’ Wnt that does not stabilise beta-catenin but plays important roles in other tissues during development. We found that Wnt-11 promotes prostate tumour cell survival, migration and differentiation into neuroendocrine-like cells (Onganer et al., 2010). Since these are all hallmarks of recurrent disease, our results may provide an opportunity for novel therapies. We are presently characterising the signals downstream of Wnt-11 that mediate its effects on prostate cancer cell differentiation, migration and survival.

Wnt antagonists

Wnt antagonists are secreted proteins that block Wnt signalling either by binding to Wnts themselves (eg members of the sFRP family, which are related to the Frizzled family of Wnt receptors) or to the LRP5/6 Wnt co-receptor (eg members of the Dickkopf family). We identified two Wnt antagonist family members that are downregulated in PCa. Ectopic expression of one of these (sFRP1) inhibits AR activity in PCa cells (Kawano et al., 2009). We are currently focusing on Dkk-3, which, although not a direct Wnt antagonist, plays an important role in prostate tissue morphogenesis (Kawano et a., 2006).

Axin/GSK-3

Axin is a scaffold protein that associates with cytosolic components of the Wnt signalling pathway to promote GSK-3-dependent phosphorylation and degradation of beta-catenin. We found that GSK-3 increases AR transcriptional activity and that Axin can inhibit AR by sequestering GSK-3 (Mazor et al., 2004). In addition, we found that chemical inhibitors of GSK-3 can inhibit AR and reduce the proliferation of  prostate cancer cells, suggesting that GSK-3 inhibitors currently being developed for treatment of diabetes and neurodegenerative disease (Kypta, 2005) might also prove useful in the treatment of prostate cancer. There are two isoforms of GSK-3, alpha and beta, and experiments are underway to characterise the functions of each one in prostate cancer.