It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death.
Using a polyclonal Fer antibody directed against a C-terminal peptide, we studied its associations with cortactin, beta-catenin and p120Cas in human prostate carcinoma PC-3 cells.
beta-catenin mutations have been found not only in melanoma and prostatic carcinoma but also in hepatocellular carcinomas in human, c-myc, H-ras genes transgenic mice and chemically-induced models.
These findings implicate beta-catenin in the regulation of AR function and support a role for beta-catenin mutations in the pathogenesis of prostate cancer.
Interest in the role of beta-catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of beta-catenin results in activation of AR transcriptional activity.
Expression rates driven by osteoblast- specific fragments from the collagen1A1-promoter, the human Osteocalcin-promoter, the bone-sialoprotein promoter and the beta-catenin promoter depending on vitamin supplementation were analysed in five OS cell lines, in normal lung fibroblasts and in a non-osteoblastic prostate cancer cell line (LNCaP) by dual luciferase assays.
We therefore conclude that, in contrast to prostate cancer, mutations in the PTEN gene seem not to affect cellular distribution of the beta-catenin protein in endometrial carcinomas.
Because activating mutations in the beta-catenin gene are rare in prostate cancer, we have looked for altered expression of other components of the Wnt signaling pathway in prostate cancer cells.
Using a reporter gene approach we found overexpressed mutated beta-catenin to enhance AR-regulated probasin-promoter activity in the AR-positive prostate cancer cell line 22Rv1, particularly at low androgen levels.
In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of beta-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes.
These findings demonstrate that AR can suppress beta-catenin signaling, that the AR-beta-catenin interaction can be regulated by Pin1, and that abrogation of this interaction can enhance beta-catenin/Tcf4 signaling and contribute to aggressive biological behavior in PCa.
Wnt is a complex signaling pathway whose endpoint involves activation of transcription from LEF-1/TCF transcription factors and it is known to be involved in the development and progression of numerous human epithelial tumors including prostate cancer. beta-catenin protein, a particularly critical molecular component of canonical Wnt signaling is now known to promote androgen signaling through its ability to bind to the AR protein in a ligand-dependent fashion and to enhance the ability of liganded AR to activate transcription of androgen-regulated genes.
SOX9 message and protein levels in prostate cancer cells were increased by treatment with glycogen synthase kinase 3beta inhibitor (SB415286), and SOX9 was reduced when beta-catenin was down-regulated by small interfering RNA (siRNA), indicating that SOX9 expression in prostate cancer is regulated by Wnt/beta-catenin signaling.
For the first time we provide experimental evidence that the C-terminus of p53 plays an important role in the down-regulation of beta-catenin-mediated TCF-signalling in PCa-cell lines possibly via p53 transrepressional function.
This study establishes the functional significance of combined dysregulation of PKD1 and E-cadherin in PC and that their effect on cell growth is mediated by beta-catenin.
These observations are consistent with the nuclear co-localization of the AR and beta-Catenin shown by immunohistochemistry in human prostate cancer samples.
Although evidence of abnormal activation of the Wnt pathway in prostate cancer has been demonstrated by several groups, APC and beta-catenin mutations are infrequent.
The fat-1 gene expression inhibited prostate cancer cell proliferation via reduction of GSK-3beta phosphorylation and subsequent down-regulation of both beta-catenin and cyclin D1.
Taken together, these observations highlight the function of beta-catenin-independent Wnt signalling in the control of AR activity and provide one explanation for sFRP1 downregulation in prostate cancer.