The expression pattern of E-cadherin, -catenin, and N-cadherin was evaluated after exposure of cells to DHT (1 nM)

The expression pattern of E-cadherin, -catenin, and N-cadherin was evaluated after exposure of cells to DHT (1 nM). 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-, 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. Keywords:cytoskeleton reorganization, actin, talin, cofilin, metastasis, TGF- signaling Prostate cancer is the mostfrequently diagnosed nonskin cancer and the third leading cause of cancer mortality among men in the United States(1). Prostate cancer mortality is primarily due to failure SPP to cure patients with metastatic disease. In the initial stages, prostate cancer is dependent on androgens for growth and can be suppressed by androgen deprivation therapy (ADT)(2). Prostate tumors, however, eventually recur due to a transition from androgen-dependent to an androgen-independent state leading to highly metastatic disease for which there is no effective therapy available. Androgen action proceedsviaan axis involving testicular synthesis of testosterone, its transport to target tissues, and its conversion by 5-reductase to the active metabolite 5-dihydrotestosterone (DHT). Androgens exert their biological effects by binding to the androgen receptor (AR) and inducing its transcriptional activity. The 5-reductase enzyme is present in the urogenital sinus before and during prostate development(3, 4), and its inhibition during fetal Rabbit Polyclonal to Cytochrome P450 26C1 development SPP results in partial prostate SPP development(5). In adult males, androgens promote secretory epithelial cell survival, the cells primarily transformed in tumor development(6). Androgen deprivation is the only clinically effective therapy for advanced prostate cancer; however, because of the relapse of castration-resistant androgen-independent tumors, the long-term benefit of androgen deprivation in patients with metastatic disease has been debated(7,8,9). The process of epithelial-mesenchymal transition (EMT) is a critical event during embryonic development, required for morphogenetic movements during parietal endoderm formation, gastrulation, and formation of organs and tissues (e.g., neural crest, heart, and craniofacial structures)(10). A growing body of recent evidence links EMT to tumor progression and metastasis. Loss of epithelial-cell markers (e.g., E-cadherin and -catenin) and gain of mesenchymal-cell markers (e.g., N-cadherin and vimentin), particularly at the leading edge or invasive front of solid tumors, has been reported in human tumor specimens and is associated with tumor progression to metastasis(11). Epithelial tumor cells lose cell polarity and cell-junction proteins and at the same time acquire protein mesenchymal-cell markers (e.g., N-cadherin and vimentin) and signaling activities associated with mesenchymal cells facilitating migration and survival in an anchorage-independent environment and ultimately metastasis(11, 12). SPP Pathological EMT in tumor cells results from transcriptional reprogramming of abnormal survival signalsviareceptors, such as platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), transform growth factor- receptor (TGF-R), and insulin-like SPP growth factor-1 receptor (IGF-1R); and regulatory kinases, such as PI3K, AKT, and mTOR(13, 14). TGF- is a potent EMT inducer in normal development and organ homeostasis, as well as during tumor progression(15). TGF- induces EMTviaSmad-dependent and Smad-independent transcriptional pathways(16). Thus Smad-mediated induction ofSnail, Slug, andTwist viaHMGA2 (high-motility group A2) and Smad-independent phosphorylation of Par6 contribute to dissolution of cell-junction complexes(17, 18). Furthermore, EMT recruits the cooperation between oncogenic Ras and receptor tyrosine kinases (RTKs) to induce downstream Raf/MAPK signaling associated with tumor progression and poor clinical diagnosis(19). We previously demonstrated a functional interplay between androgens and TGF- signaling toward enhanced apoptosis in androgen-sensitive prostate cancer cells(20). Because tumor epithelial cells gain the ability.