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J. Biol. Chem., Vol. 281, Issue 40, 29938-29948, October 6, 2006

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Androgen Induction of Prostate Cancer Cell Invasion Is Mediated by Ezrin^*

Yin-Choy Chuan, See-Tong Pang^¶, Angel Cedazo-Minguez^||, Gunnar Norstedt, Åke Pousette, and Amilcar Flores-Morales¹

From the Department of Molecular Medicine and Surgery, ^||Section of Experimental Geriatrics, Karolinska Institute, Neurotec, and Andrology Center, Department of Medicine, Karolinska Institute, 17176 Stockholm, Sweden and ^¶Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan 333, Taiwan

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 androgen-induced 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.

Received for publication, March 9, 2006 , and in revised form, July 26, 2006.

^* This work was supported by grants from the foundations of the Karolinska Institute, Cancerfonden (45576-B01-01XAB), and Swedish Research Council (529-2002-6766). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Medicine and Surgery, CMM L8:01, Karolinska Hospital, 17176 Stockholm, Sweden. Tel.: 46-8-51772089; Fax: 46-8-51556180; E-mail: Amilcar.Flores{at}cmm.ki.se.

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