N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer

Abstract

Androgen-deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. One factor that has been implicated in the metastatic process is the cell adhesion molecule N-cadherin. In this study, we investigated if the expression of N-cadherin was influenced by androgen deprivation and was associated with metastasis in prostate cancer. The effect of androgen deprivation on N-cadherin expression was initially studied in androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 and PC-3 prostate cancer cell lines. Expression of N-cadherin increased in the absence of androgens in AI LNCaP-19 primary tumors and metastases and also in vitro, but not in AI PC-3 tumors, indicating a possible involvement of the androgen receptor in the regulation of N-cadherin. N-cadherin was absent in AD LNCaP tumors. No clear associations between N-cadherin and factors related with epithelialmesenchymal transition or neuroendocrine differentiation could be established. In addition, N-cadherin was evaluated by immunohistochemistry in human prostate tumors. Expression of N-cadherin was more frequently found in tumors from patients treated with ADT than in tumors from patients with no prior hormonal treatment. N-cadherin expression was also associated with metastasis and Gleason score. Furthermore, increased N-cadherin was detected in prostate cancer biopsies already 3 months after initiation of ADT when tumors were in a regressed state. In summary the results indicate that androgen deprivation induces N-cadherin in prostate tumors. Moreover, N-cadherin was increased in castration-resistant tumors in patients with established metastases. This might indicate that castration induces molecular alterations in the tumor cells, resulting in a more invasive and metastatic phenotype.

Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer

“…Disruption of androgen signaling by ADT may result in the deregulation of cell cycle control, which could contribute to carcinogenesis. 26 Nelson et al provided four molecular-state frameworks for AR activation in PCa after ADT as follows: state 1 = endocrine androgen dependent and AR dependent; state 2 = intracrine androgen dependent and AR dependent; state 3 = androgen independent and AR dependent; and state 4 = androgen independent and AR independent. 27 State 4 is considered the fatal stage, at which AR signaling is abolished and neuroendocrine (NE) differentiation occurs.…”

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

“…EMT is typically characterized by the loss of epithelial (i.e., CDH1) and the gain of mesenchymal (i.e., VIM, CDH2) markers expression (36). Several reports suggest that AR activation, as well as androgen deprivation therapy, may induce changes characteristic of EMT that may be involved in prostate cancer progression (37)(38)(39). The expression of the transcription factor ZEB1 may be induced by dihydrotestosterone and is mediated by two androgen-response elements (40).…”

Proteomic Profiling of Androgen-independent Prostate Cancer Cell Lines Reveals a Role for Protein S during the Development of High Grade and Castration-resistant Prostate Cancer

“…In total, we identified a 3110-non-redundant protein data set, which, to our knowledge, is the most comprehensive one to date. To internally validate our approach, we observed among our top candidates, 12 proteins (MGAT5, PAM, GBA, ROBO1, CD59, MMP1, IGFBP4, CDH2, TGFB2, ICAM1, EPHA2, and IGFBP5) that have previously been studied or implicated in prostate cancer progression (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). For example, MGAT5 has been shown to mediate enhanced invasion and metastatic potential for prostate cancer cells through many in vitro invasion assays and xenograft animal models.…”