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J. Biol. Chem., Vol. 281, Issue 30, 20891-20901, July 28, 2006

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Diverse Antiapoptotic Signaling Pathways Activated by Vasoactive Intestinal Polypeptide, Epidermal Growth Factor, and Phosphatidylinositol 3-Kinase in Prostate Cancer Cells Converge on BAD^*

Konduru S. R. Sastry, Adrienne Joy Smith, Yelena Karpova, Sandeep Robert Datta, and George Kulik¹

From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157 and the Center for Neurobiology and Behavior, Columbia University, New York, New York 10032

It has been demonstrated that vasoactive intestinal polypeptide, epidermal growth factor, and chronic activation of phosphatidylinositol 3-kinase can protect prostate cancer cells from apoptosis; however, the signaling pathways that they use and molecules that they target are unknown. We report that vasoactive intestinal polypeptide, epidermal growth factor, and phosphatidylinositol 3-kinase activate independent signaling pathways that phosphorylate the proapoptotic protein BAD. Vasoactive intestinal polypeptide operated via protein kinase A, epidermal growth factor required Ras activity, and effects of phosphatidylinositol 3-kinase were predominantly mediated by Akt. BAD phosphorylation was critical for the antiapoptotic effects of each signaling pathway. None of these survival signals was able to rescue cells that express BAD with mutations in phosphorylation sites, whereas knockdown of BAD expression with small hairpin RNA rendered cells insensitive to apoptosis. Taken together, these results identify BAD as a convergence point of several antiapoptotic signaling pathways in prostate cells.

Received for publication, March 28, 2006 , and in revised form, May 12, 2006.

^* This work was supported by Department of Defense Grant DAMD17-02-1-0154, Grants form the Comprehensive Cancer Center and WFUSM Interim Funding. 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 To whom correspondence should be addressed: Dept. of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157. Tel.: 336-713-7650; Fax: 336-713-7661; E-mail: gkulik{at}wfubmc.edu.

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