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

ISSN Print: 2151-8017
ISSN Online: 2151-8025

Archives: Volume 1, 2010 to Volume 7, 2016

Forum on Immunopathological Diseases and Therapeutics

DOI: 10.1615/ForumImmunDisTher.v2.i2.90
pages 179-188

Unique Pattern of Overexpression of Raf-1 Kinase Inhibitory Protein in Its Inactivated Phosphorylated Form in Human Multiple Myeloma

Stavroula Baritaki
Department of Microbiology and Molecular Genetics, David Geffen School of Medicine, Jonnson Comprehensive Cancer Center, University of California(UCLA), USA
Sara Huerta-Yepez
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, USA; Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, SSA, Mexico City, Mexico
Ma da Lourdas Cabrava-Haimandez
Servicio da Patologia, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico
Marialuisa Sensi
Department of Experimental Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
Silvana Canevari
Fondazione IRCCS Istituto Nazionale dei Tumori; Unit of Molecular Therapies, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Massimo Libra
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Manuel Penichet
Division of Surgical Oncology, Department of Surgery, UCLA David Geffen School of Medicine; The Jonsson Comprehensive Cancer Center, The Molecular Biology Institute, Department of Microbiology, Immunology, and Molecular Genetics, UCLA
Haiming Chen
Institute for Myeloma and Bone Cancer Research, West Hollywood, CA, USA
James R. Berenson
Institute for Myeloma and Bone Cancer Research, West Hollywood, CA, USA
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

ABSTRACT

Multiple myeloma (MM) is the second most common hematological and incurable malignancy of plasma cells with low proliferative activity in the bone marrow. MM patients initially respond to conventional therapy, however, many develop resistance and recurrences occur. We have identified RKIP as a novel gene product that is differentially overexpressed in MM cell lines and MM tissues compared to other studied tumors and normal bone marrow. This overexpression consisted, in large part, of a phosphorylated inactive form of RKIP at Ser153 (p-Ser153 RKIP). In contrast to RKIP, p-Ser153 RKIP lacks its ability to inhibit the MAPK signaling pathway. The overexpression of p-Ser153 RKIP in MM cell lines and MM tissues was further validated in a mouse model carrying a human MM xenograft, namely, LAGλ-1B. Bioinformatic analyses from databases support the presence of increased RKIP mRNA expression in MM compared to normal plasma cells. In these databases, high RKIP levels in MM are also correlated with the nonhyperdiploid status and the presence of IgH translocations, parameters that generally display more aggressive clinical features and shorter patients’ survival irrespective of the treatment. Since RKIP expression regulates both the NF-κB and MAPK survival pathways, the overexpression of "inactive" p-Ser153 RKIP in MM might contribute positively to the overall cell survival/antiapoptotic phenotype and drug resistance of MM through the constitutive activation of survival pathways and downstream the transcription of anti-apoptotic gene products. The overexpression of RKIP and p-Ser153 RKIP in MM is the first demonstration in the literature, since in most tumor tissues the expression of RKIP is very low and the expression of p-Ser153 RKIP is much lower. The relationship between the levels of active RKIP and inactive p-Ser153 RKIP in MM may be of prognostic significance, and the regulation of RKIP activity may be a target for therapeutic intervention.