Androgen Induction of Prostate Cancer Cell Invasion Is Mediated by Ezrin

Abstract

Ezrin is a key signaling molecule that regulates cell survival, adhesion migration, and invasion. We have previously shown that ezrin is regulated by androgen in rat prostate and that its expression is increased in prostate cancer and in prostate intraepithelial neoplasia. We have used the androgen-sensitive cell line LNCaP-FGC to investigate the role of ezrin in androgeninduced cell invasion. We found that androgen treatment of LNCaP-FGC cells induces ezrin expression, an effect that is inhibited by the androgen receptor antagonist, bicalutamide. In addition, androgen treatment induces the phosphorylation of ezrin in Thr-567 and Tyr-353 in a sequential manner. This is mediated through protein kinase C ␣ and Src tyrosine kinase, respectively. Androgen treatment induces the translocation of both protein kinase C ␣ and ezrin to the cell membrane and their association. Inhibition of ezrin function using short interference RNA or the overexpression of T567A and Y353F-ezrin mutants significantly reduces androgen-induced Matrigel invasion but does not affect cell proliferation or cell adhesion. Matrigel invasion of the androgen-insensitive prostate cancer cell lines PC-3 and LNCaP-R is also dependent on ezrin. In summary, we have shown that androgens regulate ezrin at transcriptional and posttranscriptional levels. Hormonal regulation of ezrin phosphorylation is required for androgen-induced cell invasion. Prostate cancer (PCa)2 remains a leading cause of mortality worldwide. Despite important progress in the early diagnosis of prostate neoplasias through the measurement of prostate-specific antigen levels, ϳ10% of newly diagnosed patients have some evidence of locally advanced PCa and 5% already have distant metastasis at the time of diagnoses (1-3). Postmortem analysis of deaths attributed to PCa reveals that most subjects have evidence of metastatic disease (4). Some treatment alternatives exist with curative potential in the case of locally advanced PCa (5-7). In contrast, patients with evidence of distant metastasis have a very poor prognosis and no curative treatment exists (8).Androgen ablation therapy in its many modalities has been a mainstay in the treatment of prostatic adenocarcinoma. In general, androgen deprivation induces remission in 80 -90% of men with advanced PCa and results in a median progressionfree survival of 12-33 months. This period is usually followed by the emergence of an androgen-independent PCa resulting in a median overall survival of 23-37 months. In metastatic PCa disease, androgen ablation is also the first line of treatment. Androgen ablation in combination with external beam radiotherapy or prostatectomy delays disease progression and results in significant survival advantage when compared with radiation therapy or prostatectomy alone (5-7, 9).It is not entirely clear how hormone refractory cancer develops (10, 11). One hypothesis is that some of the mechanisms that are normally under androgen control become constitutively active in androgen-independent cells. This is supported by ...

Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

“…Ezrin Ezrin and hepatocellular carcinoma D Okamura et al is highly expressed in several types of human cancers and correlations between its immunoreactivity and patient outcome have been shown. 28 Several in vitro 29,30 studies have demonstrated that ezrin is involved in cancer cell invasion, migration, adhesion and proliferation, which may contribute to aggressive tumor progression and early recurrence after surgery. In hepatocellular carcinoma, Zhang et al 14 have reported that ezrin expression was obviously upregulated in several cell lines with high metastatic potential, including MHCC97-H, in which CK19 expression was also identified, 31 and was associated with cell proliferation, migration, and invasiveness.…”

Ezrin mediates c-Myc actions in prostate cancer cell invasion

“…As shown in Figures 1a and b, treatment of LNCaP-FGC PCa cells with synthetic androgen R1881 increased c-Myc mRNA and protein levels within 2 h of treatment and this effect was sustained for at least 8 h. The effect of R1881 was blocked by the AR antagonist bicalutamide, indicating the involvement of the AR. Because ezrin is required for androgen-induced invasion (Chuan et al, 2006), we measured ezrin levels in c-Myc expressing cells. As we have previously demonstrated, androgens treatment increases ezrin levels (Chuan et al, 2006).…”

“…Because ezrin is required for androgen-induced invasion (Chuan et al, 2006), we measured ezrin levels in c-Myc expressing cells. As we have previously demonstrated, androgens treatment increases ezrin levels (Chuan et al, 2006). This effect could be mimicked by c-Myc overexpression alone, in the absence of hormone, and was enhanced on androgen treatment ( Figure 1c).…”

“…The androgens effect on PCa cell invasion requires the activation of ezrin. This is achieved by a dual mechanism where androgens induces ezrin gene expression and the posttranslational activation of ezrin through PKCa and Src kinases (Chuan et al, 2006). Studies have shown a positive correlation of ezrin expression levels with Gleason score and seminal vesicle invasion (Pang et al, 2004a).…”

“…Studies have shown a positive correlation of ezrin expression levels with Gleason score and seminal vesicle invasion (Pang et al, 2004a). The induction of ezrin gene expression by androgens is exerted indirectly and requires a de novo synthesis of an effector molecule that is yet unknown (Chuan et al, 2006). Because of the importance of the c-Myc protein in PCa progression, we hypothesized that c-Myc could have a role in ezrin regulation.…”