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J. Biol. Chem., Vol. 279, Issue 17, 17515-17523, April 23, 2004

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RKIP Sensitizes Prostate and Breast Cancer Cells to Drug-induced Apoptosis^*

From the ^aDepartment of Medicine, Brown University and Rhode Island Hospital, Providence, Rhode Island 02903, ^cDepartment of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43614-5804, ^dCytokine Research Section, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, ^eDepartment of Biology, University of Miami, Coral Gables, Florida 33146, ^fLaboratory of Pharmacology-Pharmacotechnology, 11BEAA Soranou Efessiou 4, Athens 11527, Greece, ⁱDepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, and ^gDepartment of Pathology, University of Michigan, Ann Arbor, Michigan 48109-0940

Cancer cells are more susceptible to chemotherapeutic agent-induced apoptosis than their normal counterparts. Although it has been demonstrated that the increased sensitivity results from deregulation of oncoproteins during cancer development (Evan, G. I., and Vousden, K. H. (2001) Nature 411, 342–348; Green, D. R., and Evan, G. I. (2002) Cancer Cell 1, 19–30), little is known about the signaling pathways leading to changes in the apoptotic threshold in cancer cells. Here we show that low RKIP expression levels in tumorigenic human prostate and breast cancer cells are rapidly induced upon chemotherapeutic drug treatment, sensitizing the cells to apoptosis. We show that the maximal RKIP expression correlates perfectly with the onset of apoptosis. In cancer cells resistant to DNA-damaging agents, treatment with the drugs does not up-regulate RKIP expression. However, ectopic expression of RKIP resensitizes DNA-damaging agent-resistant cells to undergo apoptosis. This sensitization can be reversed by up-regulation of survival pathways. Down-regulation of endogenous RKIP by expression of antisense and small interfering RNA (siRNA) confers resistance on sensitive cancer cells to anticancer drug-induced apoptosis. Our studies suggest that RKIP may represent a novel effector of signal transduction pathways leading to apoptosis and a prognostic marker of the pathogenesis of human cancer cells and tumors after treatment with clinically relevant chemotherapeutic drugs.

Received for publication, December 17, 2003 , and in revised form, January 14, 2004.

^* This work was supported in part by National Institutes of Health Grant R01 GM64767 (to K. C. Y.). 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.

^b Support was provided by the T. J. Martell Foundation (to D. C. and J. D.) and a Lifespan Developmental Grant (to D. C.).

^h Supported in part by awards from the Stuart and Barbara Padnos Endowed Research Fund of the University of Michigan Comprehensive Cancer Center and the Association for the Cure of Cancer of the Prostate.

^j To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Medical College of Ohio, 3035 Arlington Ave., Toledo, OH 43614-5804. E-mail: kyeung{at}mco.edu.

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