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J. Biol. Chem. 278 (39): 37569-37573

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Targeting G{beta}{gamma} Signaling to Inhibit Prostate Tumor Formation and Growth*

Angela L. Bookout {ddagger}, Amanda E. Finney {ddagger}, Rishu Guo {ddagger}, Karsten Peppel §, Walter J. Koch {ddagger}, and Yehia Daaka {ddagger} ¶ ||

Departments of {ddagger}Surgery, §Medicine, and Pharmacology/Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

Abstract: Prostate cancer starts as androgen-dependent malignancy and responds initially to androgen ablative therapy. Beneficial effects of androgen ablation, however, are often temporary and the cancer reappears as androgen-independent tumor, suggesting the existence of additional factors responsible for progression of the disease. Attention has focused on receptor tyrosine kinases as the growth mediators of androgen-independent prostate cancer; overexpression of epidermal growth factor receptors or their ligand heparin-bound epidermal growth factor, for example, promotes transition to androgen independence. Emerging data demonstrate involvement of another class of cell membrane-anchored receptors, the heterotrimeric guanine-binding (G) protein-coupled receptors (GPCRs) in prostate cancer. In vitro, stimulation of many endogenous GPCRs induces mitogenic signaling and growth of prostate cancer cells. The GPCRs transduce mitogenic signals via activated G proteins in the form of G{alpha}-GTP and G{beta}{gamma} subunits. Here, we show that expression of a G{beta}{gamma} inhibitor peptide derived from carboxy terminus of G protein-coupled receptor kinase 2 obliterates serum-regulated prostate cancer cell growth in vitro and prevents prostate tumor formation in vivo. We also demonstrate that inhibition of G{beta}{gamma} signaling retards growth of existing prostate tumors by inducing cell death. These data establish a central role for heterotrimeric G proteins in prostate cancer and suggest targeted inhibition of G{beta}{gamma} signaling may serve as specific molecular therapy tool to limit pathologic growth of advanced prostate cancer.

Received for publication June 13, 2003. Revision received July 8, 2003.

* This work was supported by Grants AG17952 and DK60917 from the National Institutes of Health (to Y. D.). 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.

|| To whom correspondence should be addressed: Dept. of Surgery, Duke University Medical Center, Box 2607, Durham, NC 27710. Tel.: 919-684-8440; Fax: 919-684-9990; E-mail: daaka001{at}

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