Recent insights into the regulation of the androgen receptor (AR) activity led to novel therapeutic targeting of AR function in prostate cancer patients. Docetaxel is an approved chemotherapy for treatment of castration-resistant prostate cancer; however, the mechanism underlying the action of this tubulin-targeting drug is not fully understood. This study investigates the contribution of microtubules and the cytoskeleton to androgen-mediated signaling and the consequences of their inhibition on AR activity in human prostate cancer. Tissue microarrays from docetaxel-treated and untreated prostate cancer patients were comparatively analyzed for prostate-specific antigen (PSA) and AR immunoreactivity. The AR transcriptional activity was determined in prostate cancer cells in vitro, based on PSA mRNA expression and the androgen response element reporter activity. The interaction of AR with tubulin was examined by immunoprecipitation and immunofluorescence. Treatment of prostate cancer patients with docetaxel led to a significant translocation of AR. In untreated specimens, 50% prostate tumor cells exhibited nuclear accumulation of AR, compared with docetaxel-treated tumors that had significantly depleted nuclear AR (38%), paralleled by an increase in cytosolic AR. AR nuclear localization correlated with PSA expression. In vitro, exposure of prostate cancer cells to paclitaxel (1 μmol/L) or nocodazole (5 μg/mL) inhibited androgen-dependent AR nuclear translocation by targeting AR association with tubulin. Introduction of a truncated AR indicated the requirement of the NH₂-terminal domain for AR-tubulin interaction. Our findings show that in addition to blocking cell division, docetaxel impairs AR signaling, evidence that enables new insights into the therapeutic efficacy of microtubule-targeting drugs in prostate cancer. Cancer Res; 70(20); 7992–8002. ©2010 AACR.

Androgens promote the growth and differentiation of prostate cells through ligand activation of the androgen receptor (AR). Sensitization of the androgenic response by multifunctional growth factor signaling pathways is one of the mechanisms via which AR contributes to the emergence of androgen-independent prostate tumors. The ability of AR to cross-talk with key growth factor signaling events toward the regulation of cell cycle, apoptosis, and differentiation outcomes in prostate cancer cells is established. In this paper, we review the functional interaction between AR and an array of growth factor signal transduction events (including epidermal growth factor; fibroblast growth factor; IGF1; vascular endothelial growth factor; transforming growth factor-β) in prostate tumors. The significance of this derailed cross-talk between androgens and key signaling networks in prostate cancer progression and its value as a therapeutic forum targeting androgen-independent metastatic prostate cancer is discussed.

Talin1 is a focal adhesion complex protein that regulates integrin interactions with ECM. This study investigated the significance of talin1 in prostate cancer progression to metastasis in vitro and in vivo. Talin1 overexpression enhanced prostate cancer cell adhesion, migration, and invasion by activating survival signals and conferring resistance to anoikis. ShRNA-mediated talin1 loss led to a significant suppression of prostate cancer cell migration and transendothelial invasion in vitro and a significant inhibition of prostate cancer metastasis in vivo. Talin1-regulated cell survival signals via phosphorylation of focal adhesion complex proteins, such as focal adhesion kinase and Src, and downstream activation of AKT. Targeting AKT activation led to a significant reduction of talin1-mediated prostate cancer cell invasion. Furthermore, talin1 immunoreactivity directly correlated with prostate tumor progression to metastasis in the transgenic adenocarcinoma mouse prostate mouse model. Talin1 profiling in human prostate specimens revealed a significantly higher expression of cytoplasmic talin1 in metastatic tissue compared with primary prostate tumors (P < 0.0001). These findings suggest (a) a therapeutic significance of disrupting talin1 signaling/focal adhesion interactions in targeting metastatic prostate cancer and (b) a potential value for talin1 as a marker of tumor progression to metastasis. Cancer Res; 70(5); 1885–95

Androgens are functionally required for the normal growth of the prostate gland and in prostate tumor development and progression. Epithelial‐mesenchymal‐transition (EMT) is an important process during normal development and in cancer cell metastasis induced by factors within the microenvironment, such as transforming growth factor‐ß (TGF‐ß). This study examined the ability of androgens to influence EMT of prostate cancer epithelial cells. The EMT pattern was evaluated on the basis of expression of the epithelial markers E‐cadherin/ß‐catenin, and the mesenchymal markers N‐cadherin, as well as cytoskeleton reorganization in response to 5α‐dihydrotestosterone (DHT; 1 nM) and/or TGF‐ß (5 ng/ml). Overexpressing and silencing approaches to regulate androgen receptor (AR) expression were conducted to determine the involvement of AR in EMT in the presence or absence of an AR antagonist. Our results demonstrate that androgens induce the EMT pattern in prostate tumor epithelial cell with Snail activation and lead to significant changes in prostate cancer cell migration and invasion potential. Expression levels of AR inversely correlated with androgen‐mediated EMT in prostate tumor epithelial cells, pointing to a low AR content required for the EMT phenotype. These findings indicate the ability of androgens to induce EMT by potentially bypassing the functional involvement of TGF‐ß, thus contributing to metastatic behavior of prostate cancer cells.—Zhum, M.‐L., Kyprianou, N. Role of androgens and the androgen receptor in epithelial‐mesenchymal transition and invasion of prostate cancer cells. FASEB J. 24, 769–777 (2010). www.fasebj.org

Anoikis is a unique mode of apoptotic cell death that occurs consequentially to insufficient cell-matrix interactions. Resistance to anoikis is a critical contributor to tumor invasion and metastasis. The phenomenon is regulated by integrins, which upon engagement with components of the extracellular matrix (ECM) form adhesion complexes and the actin cytoskeleton drives the formation of cell protrusions used to adhere to ECM, directing cell migration. The epithelial-mesenchymal transition (EMT) confers stem cell properties and leads to acquisition of a migratory and invasive phenotype by causing adherens junction breakdown and circumventing anoikis in the tumor microenvironment. The investigation of drug discovery platforms for apoptosis-driven therapeutics identified several novel agents with antitumor action via reversing resistance to anoikis, inhibiting survival pathways and impacting the EMT landscape in human cancer. In this review, we discuss current evidence on the contribution of the anoikis phenomenon functionally linked to EMT to cancer metastasis and the therapeutic value of antitumor drugs that selectively reverse anoikis resistance and/or EMT to impair tumor progression toward the development/optimization of apoptosis-driven therapeutic targeting of metastatic disease.