• Histone Deacetylase SIRT1 Mediates C5b-9-Induced Cell Cycle in Oligodendrocytes

      Tatomir, A.; Rao, G.; Boodhoo, D.; Vlaicu, S.I.; Beltrand, A.; Anselmo, F.; Rus, V.; Rus, H. (Frontiers Media S.A., 2020)
      Sublytic levels of C5b-9 increase the survival of oligodendrocytes (OLGs) and induce the cell cycle. We have previously observed that SIRT1 co-localizes with surviving OLGs in multiple sclerosis (MS) plaques, but it is not yet known whether SIRT1 is involved in OLGs survival after exposure to sublytic C5b-9. We have now investigated the role of SIRT1 in OLGs differentiation and the effect of sublytic levels of C5b-9 on SIRT1 and phosphorylated-SIRT1 (Ser27) expression. We also examined the downstream effects of SIRT1 by measuring histone H3 lysine 9 trimethylation (H3K9me3) and the expression of cyclin D1 as a marker of cell cycle activation. OLG progenitor cells (OPCs) purified from the brain of rat pups were differentiated in vitro and treated with sublytic C5b-9 or C5b6. To investigate the signaling pathway activated by C5b-9 and required for SIRT1 expression, we pretreated OLGs with a c-jun antisense oligonucleotide, a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002), and a protein kinase C (PKC) inhibitor (H7). Our data show a significant reduction in phospho-SIRT1 and SIRT1 expression during OPCs differentiation, associated with a decrease in H3K9me3 and a peak of cyclin D1 expression in the first 24 h. Stimulation of OLGs with sublytic C5b-9 resulted in an increase in the expression of SIRT1 and phospho-SIRT1, H3K9me3, cyclin D1 and decreased expression of myelin-specific genes. C5b-9-stimulated SIRT1 expression was significantly reduced after pretreatment with c-jun antisense oligonucleotide, H7 or LY294002. Inhibition of SIRT1 with sirtinol also abolished C5b-9-induced DNA synthesis. Taken together, these data show that induction of SIRT1 expression by C5b-9 is required for cell cycle activation and is mediated through multiple signaling pathways. Copyright 2020 Tatomir, et. al.
    • Role of C5b-9 and RGC-32 in cancer

      Vlaicu, S.I.; Tatomir, A.; Rus, V. (Frontiers Media S.A., 2019)
      The complement system represents an effective arsenal of innate immunity as well as an interface between innate and adaptive immunity. Activation of the complement system culminates with the assembly of the C5b-9 terminal complement complex on cell membranes, inducing target cell lysis. Translation of this sequence of events into a malignant setting has traditionally afforded C5b-9 a strict antitumoral role, in synergy with antibody-dependent tumor cytolysis. However, in recent decades, a plethora of evidence has revised this view, highlighting the tumor-promoting properties of C5b-9. Sublytic C5b-9 induces cell cycle progression by activating signal transduction pathways (e.g., Gi protein/ phosphatidylinositol 3-kinase (PI3K)/Akt kinase and Ras/Raf1/ERK1) and modulating the activation of cancer-related transcription factors, while shielding malignant cells from apoptosis. C5b-9 also induces Response Gene to Complement (RGC)-32, a gene that contributes to cell cycle regulation by activating the Akt and CDC2 kinases. RGC-32 is expressed by tumor cells and plays a dual role in cancer, functioning as either a tumor promoter by endorsing malignancy initiation, progression, invasion, metastasis, and angiogenesis, or as a tumor suppressor. In this review, we present recent data describing the versatile, multifaceted roles of C5b-9 and its effector, RGC-32, in cancer. Copyright Copyright 2019 Vlaicu, Tatomir, Rus and Rus.