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J. Biol. Chem., Vol. 281, Issue 36, 26483-26490, September 8, 2006

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A Role for the G₁₂ Family of Heterotrimeric G Proteins in Prostate Cancer Invasion^*

Patrick Kelly¹, Laura N. Stemmle, John F. Madden, Timothy A. Fields, Yehia Daaka^¶, and Patrick J. Casey²

From the Department of Pharmacology and Cancer Biology and Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710 and the ^¶Department of Pathology, Medical College of Georgia, Augusta, Georgia 30912

Many studies have suggested a role for the members of the G₁₂ family of heterotrimeric G proteins (G₁₂ and G₁₃) in oncogenesis and tumor cell growth. However, few studies have examined G₁₂ signaling in actual human cancers. In this study, we examined the role of G₁₂ signaling in prostate cancer. We found that expression of the G₁₂ proteins is significantly elevated in prostate cancer. Interestingly, expression of the activated forms of G₁₂ or G₁₃ in the PC3 and DU145 prostate cancer cell lines did not promote cancer cell growth. Instead, expression of the activated forms of G₁₂ or G₁₃ in these cell lines induced cell invasion through the activation of the RhoA family of G proteins. Furthermore, inhibition of G₁₂ signaling by expression of the RGS domain of the p115-Rho-specific guanine nucleotide exchange factor (p115-RGS) in the PC3 and DU145 cell lines did not reduce cancer cell growth. However, inhibition of G₁₂ signaling with p115-RGS in these cell lines blocked thrombin- and thromboxane A2-stimulated cell invasion. These observations identify the G₁₂ family proteins as important regulators of prostate cancer invasion and suggest that these proteins may be targeted to limit invasion- and metastasis-induced prostate cancer patient mortality.

Received for publication, May 8, 2006

^* This work was supported by National Institutes of Health Grants CA100869 (to P. J. C.) and AG17952 and DK60917 (to Y. D.), Department of Defense Grant DAMD17-03-1-0691 (to T. A. F.), and the Morris Cancer Center (to P. J. C.). 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 supplemental Figs. 1 and 2.

¹ Supported by the Duke University Medical School Alumni Scholarship.

² To whom correspondence should be addressed: Box 3813, Duke University Medical Center, Durham, NC 27710-3813. Tel.: 919-613-8613; Fax: 919-613-8642; E-mail: casey006{at}mc.duke.edu.

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