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* Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;
Department of Medicine, Brown University and Rhode Island Hospital, Providence, RI 02903;
Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, OH 43614; and
Department of Clinical Virology, Faculty of Medicine, University of Crete, Heraklion, Greece
Raf-1 kinase inhibitor protein (RKIP) has been implicated in the regulation of cell survival pathways and metastases, and is poorly expressed in tumors. We have reported that the NF-
B pathway regulates tumor resistance to apoptosis by the TNF-
family via inactivation of the transcription repressor Yin Yang 1 (YY1). We hypothesized that RKIP overexpression may regulate tumor sensitivity to death ligands via inhibition of YY1 and up-regulation of death receptors (DRs). The TRAIL-resistant prostate carcinoma PC-3 and melanoma M202 cell lines were examined. Transfection with CMV-RKIP, but not with control CMV-EV, sensitized the cells to TRAIL-mediated apoptosis. Treatment with RKIP small interfering RNA (siRNA) inhibited TRAIL-induced apoptosis. RKIP overexpression was paralleled with up-regulation of DR5 transcription and expression; no change in DR4, decoy receptor 1, and decoy receptor 2 expression; and inhibition of YY1 transcription and expression. Inhibition of YY1 by YY1 siRNA sensitized the cells to TRAIL apoptosis concomitantly with DR5 up-regulation. RKIP overexpression inhibited several antiapoptotic gene products such as X-linked inhibitor of apoptosis (XIAP), c-FLIP long, and Bcl-xL that were accompanied with mitochondrial membrane depolarization. RKIP overexpression in combination with TRAIL resulted in the potentiation of these above effects and activation of caspases 8, 9, and 3, resulting in apoptosis. These findings demonstrate that RKIP overexpression regulates tumor cell sensitivity to TRAIL via inhibition of YY1, up-regulation of DR5, and modulation of apoptotic pathways. We suggest that RKIP may serve as an immune surveillance cancer gene, and its low expression or absence in tumors allows the tumor to escape host immune cytotoxic effector cells.
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1 Address correspondence and reprint requests to Dr. Benjamin Bonavida, Department of Microbiology, Immunology, and Molecular Genetics, University of California, 10833 Le Conte Avenue, A2-060 CHS, Los Angeles, CA 90095-1747. E-mail address: bbonavida{at}mednet.ucla.edu
2 Abbreviations used in this paper: DR, death receptor; 2MAM-A3, 2-methoxyantimycin A3; CDDP, cis-diammine-dichloro-platinum; c-FLIP, caspase 8 FLIP; c-FLIPL, c-FLIP long; c-FLIPS, c-FLIP short; DcR, decoy receptor; DHMEQ, dehydroxymethylepoxyquinomicin; DiOC6, 3,3'-dihexyloxacarbocyanine; FasL, Fas ligand; IKK, IB kinase; MFI, mean fluorescence intensity; NIK, NF-B-inducing kinase; PI, propidium iodide; RKIP, Raf kinase inhibitor protein; si, small interfering; XIAP, X-linked inhibitor of apoptosis; YY1, Yin Yang 1; TAK1, TGF-B-activated kinase 1.
This article has been cited by other articles:
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  S. Baritaki, K. Yeung, M. Palladino, J. Berenson, and B. Bonavida Pivotal Roles of Snail Inhibition and RKIP Induction by the Proteasome Inhibitor NPI-0052 in Tumor Cell Chemoimmunosensitization Cancer Res., November 1, 2009; 69(21): 8376 - 8385. [Abstract] [Full Text] [PDF]
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