Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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}mc.duke.edu.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Expanding Roles of G{beta}{gamma} Subunits in G Protein-Coupled Receptor Signaling and Drug Action.
S. M. Khan, R. Sleno, S. Gora, P. Zylbergold, J.-P. Laverdure, J.-C. Labbe, G. J. Miller, and T. E. Hebert (2013)
Pharmacol. Rev. 65, 545-577
   Abstract »    Full Text »    PDF »
G Protein-Coupled Receptor-Mediated Activation of p110{beta} by G{beta}{gamma} Is Required for Cellular Transformation and Invasiveness.
H. A. Dbouk, O. Vadas, A. Shymanets, J. E. Burke, R. S. Salamon, B. D. Khalil, M. O. Barrett, G. L. Waldo, C. Surve, C. Hsueh, et al. (2012)
Science Signaling 5, ra89
   Abstract »    Full Text »    PDF »
The WD40 Repeat Protein WDR26 Binds G{beta}{gamma} and Promotes G{beta}{gamma}-dependent Signal Transduction and Leukocyte Migration.
Z. Sun, X. Tang, F. Lin, and S. Chen (2011)
J. Biol. Chem. 286, 43902-43912
   Abstract »    Full Text »    PDF »
Understanding Molecular Recognition by G protein {beta}{gamma} Subunits on the Path to Pharmacological Targeting.
Y. Lin and A. V. Smrcka (2011)
Mol. Pharmacol. 80, 551-557
   Abstract »    Full Text »    PDF »
A Critical Role of G{beta}{gamma} in Tumorigenesis and Metastasis of Breast Cancer.
X. Tang, Z. Sun, C. Runne, J. Madsen, F. Domann, M. Henry, F. Lin, and S. Chen (2011)
J. Biol. Chem. 286, 13244-13254
   Abstract »    Full Text »    PDF »
Rational Design of a Selective Covalent Modifier of G Protein {beta}{gamma} Subunits.
A. L. Dessal, R. Prades, E. Giralt, and A. V. Smrcka (2011)
Mol. Pharmacol. 79, 24-33
   Abstract »    Full Text »    PDF »
G{beta}{gamma} Signaling Promotes Breast Cancer Cell Migration and Invasion.
J. K. Kirui, Y. Xie, D. W. Wolff, H. Jiang, P. W. Abel, and Y. Tu (2010)
J. Pharmacol. Exp. Ther. 333, 393-403
   Abstract »    Full Text »    PDF »
NMR analysis of G-protein {beta}{gamma} subunit complexes reveals a dynamic G{alpha}-G{beta}{gamma} subunit interface and multiple protein recognition modes.
A. V. Smrcka, N. Kichik, T. Tarrago, M. Burroughs, M.-S. Park, N. K. Itoga, H. A. Stern, B. M. Willardson, and E. Giralt (2010)
PNAS 107, 639-644
   Abstract »    Full Text »    PDF »
Epinephrine Protects Cancer Cells from Apoptosis via Activation of cAMP-dependent Protein Kinase and BAD Phosphorylation.
K. S. R. Sastry, Y. Karpova, S. Prokopovich, A. J. Smith, B. Essau, A. Gersappe, J. P. Carson, M. J. Weber, T. C. Register, Y. Q. Chen, et al. (2007)
J. Biol. Chem. 282, 14094-14100
   Abstract »    Full Text »    PDF »
Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric G{alpha}/G{beta}{gamma} Protein Complex..
G. P. Prevost, M. O. Lonchampt, S. Holbeck, S. Attoub, D. Zaharevitz, M. Alley, J. Wright, M. C. Brezak, H. Coulomb, A. Savola, et al. (2006)
Cancer Res. 66, 9227-9234
   Abstract »    Full Text »    PDF »
G{beta}{gamma} Binds Histone Deacetylase 5 (HDAC5) and Inhibits Its Transcriptional Co-repression Activity.
B. D. Spiegelberg and H. E. Hamm (2005)
J. Biol. Chem. 280, 41769-41776
   Abstract »    Full Text »    PDF »
A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells.
M. Bektas, S. G. Payne, H. Liu, S. Goparaju, S. Milstien, and S. Spiegel (2005)
J. Cell Biol. 169, 801-811
   Abstract »    Full Text »    PDF »
Androgen Receptor Activation by Gs Signaling in Prostate Cancer Cells.
E. A. Kasbohm, R. Guo, C. W. Yowell, G. Bagchi, P. Kelly, P. Arora, P. J. Casey, and Y. Daaka (2005)
J. Biol. Chem. 280, 11583-11589
   Abstract »    Full Text »    PDF »
Interleukin 6 Mediates the Lysophosphatidic Acid-regulated Cross-talk between Stromal and Epithelial Prostate Cancer Cells.
P. Sivashanmugam, L. Tang, and Y. Daaka (2004)
J. Biol. Chem. 279, 21154-21159
   Abstract »    Full Text »    PDF »
G Proteins in Cancer: The Prostate Cancer Paradigm.
Y. Daaka (2004)
Sci. STKE 2004, re2
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882