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J. Biol. Chem., Vol. 279, Issue 2, 937-944, January 9, 2004

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Androgen Control of Cell Proliferation and Cytoskeletal Reorganization in Human Fibrosarcoma Cells

ROLE OF RhoB SIGNALING^*

Sanjay Chauhan, Susan Kunz, Kelli Davis, Jordan Roberts, Greg Martin, Manolis C. Demetriou¶||, Thomas C. Sroka¶||, Anne E. Cress¶||, and Roger L. Miesfeld**

From the Departments of Biochemistry and Molecular Biophysics, Molecular and Cellular Biology, ^¶Cell Biology and Anatomy, and ^||The Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85721

We recently generated an HT-1080-derived cell line called HT-AR1 that responds to dihydrotestosterone (DHT) treatment by undergoing cell growth arrest in association with cytoskeletal reorganization and induction of neuroendocrine-like cell differentiation. In this report, we show that DHT induces a dose-dependent increase in G₀/G₁ growth-arrested cells using physiological levels of hormone. The arrested cells increase in cell size and contain a dramatic redistribution of desmoplakin, keratin 5, and chromogranin A proteins. DHT-induced cytoskeletal changes were also apparent from time lapse video microscopy that showed that androgen treatment resulted in the rapid appearance of neuronal-like membrane extensions. Expression profiling analysis using RNA isolated from DHT-treated HT-AR1 cells revealed that androgen receptor activation leads to the coordinate expression of numerous cell signaling genes including RhoB, PTGF-, caveolin-2, Egr-1, myosin 1B, and EHM2. Because RhoB has been shown to have a role in tumor suppression and neuronal differentiation in other cell types, we investigated RhoB signaling functions in the HT-AR1 steroid response. We found that steroid induction of RhoB was DHT-specific and that newly synthesized RhoB protein was post-translationally modified and localized to endocytic vesicles. Moreover, treatment with a farnesyl transferase inhibitor reduced DHT-dependent growth arrest, suggesting that prenylated RhoB might function to inhibit HT-AR1 cell proliferation. This was directly shown by transfecting HT-AR1 cells with RhoB coding sequences containing activating or dominant negative mutations.

Received for publication, October 15, 2003

^* This work was supported by National Institutes of Health Grant CA 23074, Arizona Cancer Center Core Grants PO1 CA 56666 and CA 75152 (to A. E. C.), and the generous support of the Jack Findlay Doyle II Charitable Fund (to R. L. M.). 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.

The on-line version of this article (available at http://www.jbc.org) contains two video movies of HT-AR1 cells cultured in media ±DHT for 5 h as separate 5 MB QuickTime media files (HTAR1-Control.mov and HTAR1-DHT.mov).

^** To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, AZ 85721. Tel.: 520-626-2343; Fax: 520-621-1697; E-mail: RLM{at}u.arizona.edu.

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