Abstract
Prostate cancer (PCa) is a common hormone-dependent malignancy associated with the development of skeletal metastases. This is due to the increased expression of a number of growth factors, cytokines, and proteases which collectively drive the metastatic cascade in general and increased propensity to develop skeletal metastasis in particular. While a number of signaling pathways have been implicated in PCa progression, the highly complex wnt/β-catenin pathway is unique due to its ability to regulate gene expression, cell invasion, migration, survival, proliferation, and differentiation to contribute in the initiation and progression of PCa. Members of the wnt family bind to the Frizzle proteins or lipoprotein-related receptor proteins 5, 6 (LRP5, -6) to activate this key pathway. In the current study, we have investigated the role of wnt/β-catenin pathway in PCa progression, skeletal metastasis, and gene expression using the dominant negative plasmid of LRP5 (DN-LRP5) and human PCa cells PC-3. Inactivation of LRP5 resulted in mesenchymal to epithelial shift, lack of translocation of β-catenin to cell surface, increased tumor cell proliferation, decreased colony formation, migration and invasion in vitro. These effects were attributed to decreased expression of pro-invasive and pro-metastatic genes. In in vivo studies, PC-3-DN-LRP5 cells developed significantly smaller tumors and a marked decrease in skeletal lesion area and number as determined by X-ray, micro (μ) CT and histological analysis. Collectively results from these studies demonstrate the dominant role of this key pathway in PCa growth and skeletal metastasis and its potential as a viable therapeutic target.
Highlights
IntroductionIn the multistep process of tumor progress, Prostate cancer (PCa) starts as a low-invasive hormone-sensitive (androgen) cancer which over time becomes hormone insensitive and acquires an aggressive phenotype [1, 2]
Prostate cancer (PCa) is a leading cause of cancer-associated death in men
Human PCa cells PC-3 were transfected with vector alone and dominant negative plasmid of LRP5 (DN-LRP5) plasmid were maintained in culture
Summary
In the multistep process of tumor progress, PCa starts as a low-invasive hormone-sensitive (androgen) cancer which over time becomes hormone insensitive and acquires an aggressive phenotype [1, 2]. These cellular characteristics of PCa cells have led to the use of antiandrogens as standard therapy for PCa patients [1, 2]. In order to fully understand the mechanism of developing skeletal metastases and bone remodeling in PCa, the role of a number of growth factors, proteases, and cytokines have been described which are regulated via multiple intracellular signaling pathways [3,4,5,6]. Among these the Wnt/b-catenin signaling pathway which is well characterized for its role in health and disease state has been proposed as a significant player in PCa progression [9, 10]
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