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Forum on Immunopathological Diseases and Therapeutics
SJR: 0.309 SNIP: 0.041 CiteScore™: 0.18

ISSN Печать: 2151-8017
ISSN Онлайн: 2151-8025

Archives: Volume 1, 2010 to Volume 7, 2016

Forum on Immunopathological Diseases and Therapeutics

DOI: 10.1615/ForumImmunDisTher.v2.i1.110
pages 95-109

Dual Roles of Raf-1 Kinase Inhibitor Protein in the Regulation of Both Tumor Cell Resistance to Apoptotic Stimuli and Epithelial to Mesenchymal Transition

Stavroula Baritaki
Department of Microbiology and Molecular Genetics, David Geffen School of Medicine, Jonnson Comprehensive Cancer Center, University of California(UCLA), USA
Kam C. Yeung
Department of Biochemistry & Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio
Benjamin Bonavida
Department of Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747

Краткое описание

Most tumors develop several strategies to resist conventional chemotherapy as well as to escape from the host immunosurveillance mechanisms. These result in tumor persistence and spread, through activation of the epithelial to mesenchymal transition (EMT) program. The molecular bases of tumor resistance to apoptosis and EMT are thought to be due, in part, to the constitutive activation of survival signaling pathways including NF-κB. RKIP is a member of the PEBP family and it has been implicated in the negative regulation of the NF-κB and MAPK survival pathways. RKIP expression has been found significantly diminished in several tumors and almost absent in metastatic tissues, thus suggesting that RKIP may serve as a metastasis suppressor gene product. We have reported that RKIP overexpression reverses the tumor cell resistance to both chemotherapy and immunotherapy, as well as inhibits the mesenchymal cell phenotype (EMT) in metastatic tumor cell lines. In contrast, RKIP silencing by RKIP siRNA-inhibited TRAIL- or drug-induced apoptosis and induced EMT. RKIP overexpression was paralleled with upregulation of the TRAIL and Fas receptors DR5 and Fas, respectively, through inhibition of their transcriptional repressor Yin Yang 1 (YY1). YY1 siRNA resensitized the cells to TRAIL/FasL and drug apoptosis. RKIP transcription is directly repressed by Snail, a transcriptional target of NF-κB that serves as an EMT inducer through repression of E-cadherin. RKIP overexpression reduced Snail expression through NF-κB inhibition, while Snail silencing reversed both tumor resistance and EMT. Novel therapeutics such as the proteasome inhibitor NPI-0052 and the NO donor DETANONOate upregulated RKIP expression and led to tumor cell resensitization to TRAIL and inhibition of EMT. These findings demonstrate that RKIP regulates tumor cell sensitivity to apoptotic stimuli, and inhibits EMT via modulation of the dysregulated NF-κB/YY1/Snail circuitry. We propose that RKIP is a therapeutic target for intervention in the treatment of resistant and metastatic cancers.

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