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J. Biol. Chem., Vol. 282, Issue 33, 24364-24372, August 17, 2007

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Modulation of Intracellular Signaling Pathways to Induce Apoptosis in Prostate Cancer Cells^*

Jinjin Guo, Tongbo Zhu, Zhi-Xiong J. Xiao, and Chang-Yan Chen¹

From the Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 and the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

An understanding of the molecular pathways defining the susceptibility of prostate cancer, especially refractory prostate cancer, to apoptosis is the key for developing a cure for this disease. We previously demonstrated that up-regulating Ras signaling, together with suppression of protein kinase C (PKC), induces apoptosis. Dysregulation of various intracellular signaling pathways, including those governed by Ras, is the important element in the development of prostate cancer. In this study, we tested whether it is possible to modulate the activities of these pathways and induce an apoptotic crash among them in prostate cancer cells. Our data showed that DU145 cells express a high amount of JNK1 that is phosphorylated after endogenous PKC is suppressed, which initiates caspase 8 cleavage and cytochrome c release, leading to apoptosis. PC3 and LNCaP cells contain an activated Akt. The inhibition of PKC further augments Akt activity, which in turn induces ROS production and the accumulation of unfolded proteins in the endoplasmic reticulum, resulting in cell death. However, the concurrent activation of JNK1 and Akt, under the condition of PKC abrogation, dramatically augment the magnitude of apoptosis in the cells. Thus, our study suggests that Akt, JNK1, and PKC act in concert to signal the intracellular apoptotic machinery for a full execution of apoptosis in prostate cancer cells.

Received for publication, April 6, 2007 , and in revised form, June 13, 2007.

^* The work was supported by National Institutes of Health Grant RO1CA100498 and Department of Defense Grant W81XWH-04-1-0246. 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.

¹ To whom correspondence should be addressed: 21-27 Burlington Ave., Rm. 553C, Boston, MA. Tel.: 617-632-8513; Fax: 617-632-0635; E-mail: cchen6{at}bidmc.harvard.edu.

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