Androgen receptor as a driver of therapeutic resistance in advanced prostate cancer.

The role of the androgen receptor (AR) signaling axis in the progression of prostate cancer is a cornerstone to our understanding of the molecular mechanisms causing castration-resistant prostate cancer (CRPC). Resistance of advanced prostate cancer to available treatment options makes it a clinical challenge that results in approximately 30,000 deaths of American men every year. Since the historic discovery by Dr. Huggins more than 70 years ago, androgen deprivation therapy (ADT) has been the principal treatment for advanced prostate cancer. Initially, ADT induces apoptosis of androgen-dependent prostate cancer epithelial cells and regression of androgen-dependent tumors. However, the majority of patients with advanced prostate cancer progress and become refractory to ADT due to emergence of androgen-independent prostate cancer cells driven by aberrant AR activation. Microtubule-targeting agents such as taxanes, docetaxel and paclitaxel, have enjoyed success in the treatment of metastatic prostate cancer; although new, recently designed mitosis-specific agents, such as the polo-kinase and kinesin-inhibitors, have yielded clinically disappointing results. Docetaxel, as a first-line chemotherapy, improves prostate cancer patient survival by months, but tumor resistance to these therapeutic agents inevitably develops. On a molecular level, progression to CRPC is characterized by aberrant AR expression, de novo intraprostatic androgen production, and cross talk with other oncogenic pathways. Emerging evidence suggests that reactivation of epithelial-mesenchymal-transition (EMT) processes may facilitate the development of not only prostate cancer but also prostate cancer metastases. EMT is characterized by gain of mesenchymal characteristics and invasiveness accompanied by loss of cell polarity, with an increasing number of studies focusing on the direct involvement of androgen-AR signaling axis in EMT, tumor progression, and therapeutic resistance. In this article, we discuss the current knowledge of mechanisms via which the AR signaling drives therapeutic resistance in prostate cancer metastatic progression and the novel therapeutic interventions targeting AR in CRPC.

Cofilin drives cell-invasive and metastatic responses to TGF-ß in prostate cancer.

Cofilin (CFL) is an F-actin-severing protein required for the cytoskeleton reorganization and filopodia formation, which drives cell migration. CFL binding and severing of F-actin is controlled by Ser3 phosphorylation, but the contributions of this step to cell migration during invasion and metastasis of cancer cells are unclear. In this study, we addressed the question in prostate cancer cells, including the response to TGF-ß, a critical regulator of migration. In cells expressing wild-type CFL, TGF-ß treatment increased LIMK-2 activity and cofilin phosphorylation, decreasing filopodia formation. Conversely, constitutively active CFL (SerAla) promoted filipodia formation and cell migration mediated by TGF-ß. Notably, in cocultures of prostate cancer epithelial cells and cancer-associated fibroblasts, active CFL promoted invasive migration in response to TGF-ß in the microenvironment. Further, constitutively active CFL elevated the metastatic ability of prostate cancer cells in vivo. We found that levels of active CFL correlated with metastasis in a mouse model of prostate tumor and that in human prostate cancer, CFL expression was increased significantly in metastatic tumors. Our findings show that the actin-severing protein CFL coordinates responses to TGF-ß that are needed for invasive cancer migration and metastasis.

EMMPRIN regulates cytoskeleton reorganization and cell adhesion in prostate cancer.

BACKGROUND: Proteins on cell surface play important roles during cancer progression and metastasis via their ability to mediate cell-to-cell interactions and navigate the communication between cells and the microenvironment. METHODS: In this study a targeted proteomic analysis was conducted to identify the differential expression of cell surface proteins in human benign (BPH-1) versus malignant (LNCaP and PC-3) prostate epithelial cells. We identified EMMPRIN (extracellular matrix metalloproteinase inducer) as a key candidate and shRNA functional approaches were subsequently applied to determine the role of EMMPRIN in prostate cancer cell adhesion, migration, invasion as well as cytoskeleton organization. RESULTS: EMMPRIN was found to be highly expressed on the surface of prostate cancer cells compared to BPH-1 cells, consistent with a correlation between elevated EMMPRIN and metastasis found in other tumors. No significant changes in cell proliferation, cell cycle progression, or apoptosis were detected in EMMPRIN knockdown cells compared to the scramble controls. Furthermore, EMMPRIN silencing markedly decreased the ability of PC-3 cells to form filopodia, a critical feature of invasive behavior, while it increased expression of cell-cell adhesion and gap junction proteins. CONCLUSIONS: Our results suggest that EMMPRIN regulates cell adhesion, invasion, and cytoskeleton reorganization in prostate cancer cells. This study identifies a new function for EMMPRIN as a contributor to prostate cancer cell-cell communication and cytoskeleton changes towards metastatic spread, and suggests its potential value as a marker of prostate cancer progression to metastasis.

Dysfunctional transforming growth factor-beta receptor II accelerates prostate tumorigenesis in the TRAMP mouse model.

The contribution of a dysfunctional transforming growth factor-beta type II receptor (TGF beta RII) to prostate cancer initiation and progression was investigated in an in vivo mouse model. Transgenic mice harboring the dominant-negative mutant TGF-beta type II receptor (DNTGF beta RII) in mouse epithelial cell were crossed with the TRAMP prostate cancer transgenic mouse to characterize the in vivo consequences of inactivated TGF-beta signaling on prostate tumor initiation and progression. Histopathologic diagnosis of prostate specimens from the TRAMP+/DNTGF beta RII double transgenic mice revealed the appearance of early malignant changes and subsequently highly aggressive prostate tumors at a younger age, compared with littermates TRAMP+/Wt TGF beta RII mice. Immunohistochemical and Western blotting analysis revealed significantly increased proliferative and apoptotic activities, as well as vascularity and macrophage infiltration that correlated with an elevated vascular endothelial growth factor and MCP-1 protein levels in prostates from TRAMP+/DNTGF beta RII+ mice. An epithelial-mesenchymal transition (EMT) effect was also detected in prostates of TRAMP+/DNTGF beta RII mice, as documented by the loss of epithelial markers (E-cadherin and beta-catenin) and up-regulation of mesenchymal markers (N-cadherin) and EMT-transcription factor Snail. A significant increase in the androgen receptor mRNA and protein levels was associated with the early onset of prostate tumorigenesis in TRAMP+/DNTGF beta RII mice. Our results indicate that in vivo disruption of TGF-beta signaling accelerates the pathologic malignant changes in the prostate by altering the kinetics of prostate growth and inducing EMT. The study also suggests that a dysfunctional TGF beta RII augments androgen receptor expression and promotes inflammation in early stage tumor growth, thus conferring a significant contribution by TGF-beta to prostate cancer progression.