Role of C5b-9 complement complex and response gene to complement-32 (RGC-32) in cancer
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Role of C5b-9 complement complex and response gene to complement-32 (RGC-32) in cancer Sonia I. Vlaicu • Cosmin A. Tegla • Cornelia D. Cudrici • Jacob Danoff • Hassan Madani • Adam Sugarman • Florin Niculescu Petru A. Mircea • Violeta Rus • Horea Rus
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Published online: 18 December 2012 Ó Springer Science+Business Media New York 2012
Abstract Complement system activation plays an important role in both innate and acquired immunity, with the activation of complement and the subsequent formation of C5b-9 terminal complement complex on cell membranes inducing target cell death. Recognition of this role for C5b-9 leads to the assumption that C5b-9 might play an antitumor role. However, sublytic C5b-9 induces cell cycle progression by activating signal transduction pathways and transcription factors in cancer cells, indicating a role in tumor promotion for this complement complex. The induction of the cell cycle by C5b-9 is dependent upon the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/ FOXO1 and ERK1 pathways in a Gi protein-dependent manner. C5b-9 also induces response gene to complement S. I. Vlaicu C. A. Tegla C. D. Cudrici J. Danoff H. Madani A. Sugarman H. Rus (&) Department of Neurology, University of Maryland School of Medicine, 655W. Baltimore Street, BRB 12-033, Baltimore, MD 21201, USA e-mail: [email protected] S. I. Vlaicu P. A. Mircea Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Medical Clinic No. 1, Cluj-Napoca, Romania C. A. Tegla H. Rus Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA F. Niculescu V. Rus Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD, USA H. Rus Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA
(RGC)-32, a gene that plays a role in cell cycle promotion through activation of Akt and the CDC2 kinase. RGC-32 is expressed by tumor cells and plays a dual role in cancers, in that it has both a tumor suppressor role and tumor-promoting activity. Thus, through the activation of tumor cells, the C5b-9-mediated induction of the cell cycle plays an important role in tumor proliferation and oncogenesis. Keywords C5b-9 RGC-32 Cancer Cell cycle Signal transduction Transcription factors
Introduction The process of carcinogenesis in human cells begins as a sequence of steps involving genetic or epigenetic alterations and concluding with the formation of a malignant cell that is fully prepared to resist most anticancer defense mechanisms. Hanahan and Weinberg have identified six essential alterations in the cancerous cell: (a) self-sufficiency in growth signals, (b) insensitivity to antigrowth signals, (c) evasion of apoptosis, (d) limitless replicative potential, (e) sustained angiogenesis, and (f) tissue invasion and metastasis [1]. Recent studies have proposed that cancer-related inflammation (CRI) is a seventh feature of cancer [2, 3]. Virchow first pointed
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