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J. Biol. Chem., Vol. 281, Issue 49, 37330-37344, December 8, 2006

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Molecular Mechanism of Adaphostin-mediated G₁ Arrest in Prostate Cancer (PC-3) Cells

SIGNALING EVENTS MEDIATED BY HEPATOCYTE GROWTH FACTOR RECEPTOR, c-Met, AND p38 MAPK PATHWAYS^*

Indranil Mukhopadhyay¹, Edward A. Sausville, James H. Doroshow, and Krishnendu K. Roy²

From the Laboratory of Clinical Trials Unit, Division of Cancer Treatment and Diagnosis, NCI, National Institutes of Health, Bethesda, Maryland 20892 and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201

Adaphostin (NSC680410), a small molecule congener of tyrphostin AG957, has been demonstrated previously to have significant anti-proliferative effects in several leukemia models. However, this effect of adaphostin in adherent cells/solid tumor models has not been examined. In this study, we investigated the anti-proliferative effects of adaphostin in the human prostate cancer cell line PC-3. Specifically, we explored the potential molecular mechanism(s) by which adaphostin elicits its anti-proliferative effect(s). We demonstrate that adaphostin inhibits the proliferation of PC-3 cells by inducing a G₁ phase cell cycle arrest. This adaphostin-induced G₁ arrest was associated with an increase in the expression of p21 and p27 and a decrease in the expression of G₁-specific cyclins (cyclin A, D1, and D3) and cyclin-dependent kinases 4 and 6. Consequently, a dramatic decrease in the phosphorylation of retinoblastoma protein was also observed. Additionally, we found that adaphostin treatment induced a decrease in the phosphorylation of nucleophosmin, a major nuclear phosphoprotein, and that this decreased phosphorylation was a result of the p21- and p27-mediated inactivation of cyclin E-cyclin-dependent kinase 2 complex kinase activity. Furthermore, we have determined that the adaphostin-mediated cell cycle arrest of PC-3 cells is dependent upon activation of the p38 MAPK. We also demonstrate that the hepatocyte growth factor receptor-c-Met is involved in the adaphostin-mediated signaling events that regulate p38 MAPK. Taken together, these results identify for the first time a signaling cascade of adaphostin-mediated G₁ phase-specific cell cycle arrest in PC-3 cells. These findings suggest that the tyrphostin member has a broader spectrum of activity than originally predicted.

Received for publication, June 9, 2006 , and in revised form, July 31, 2006.

^* 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 Present address: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bethesda, MD 20892.

² To whom correspondence should be addressed: NCI, National Institutes of Health, 37 Convent Dr., Bldg. 37, Rm. 1052, Bethesda, MD 20892. Tel.: 301-496-4119; Fax: 301-480-7456; E-mail: kr91w{at}nih.gov.

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