Role of C5b-9 and RGC-32 in Cancer

Sonia I. Vlaicu,Alexandru Tatomir,Horea Rus,Violeta Rus

doi:10.3389/fimmu.2019.01054

Abstract

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.

Highlights

Carcinogenesis in human somatic cells involves a series of genetic and epigenetic alterations that culminate in the generation of a malignant tissue fully prepared to elude most anticancer defense strategies
Cellular proliferation induced by membrane-inserted sublytic C5b-9 relies on the activation of the Gi protein/PI3K/Akt kinase and Ras/Raf-1/extracellular signal-regulated kinase 1 (ERK1) pathways and regulation of cell cyclespecific genes and proto-oncogenes [5, 47] (Figure 1)
Sublytic C5b-9 has been shown to interact with effectors of TNFα-induced necroptosis, yet another type of programmed cell death: exposure of human erythroleukemia K562 cells to sublytic C5b-9 causes the activation of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like protein (MLKL), co-localization of RIPK3 with RIPK1 in the cytoplasm and co-localization of RIPK3 and MLKL with C5b-9 at the plasma membrane [28]

Summary

Introduction

Carcinogenesis in human somatic cells involves a series of genetic and epigenetic alterations that culminate in the generation of a malignant tissue fully prepared to elude most anticancer defense strategies. SUBLYTIC C5b-9 INDUCES TUMOR CELL PROLIFERATION AND TRANSCRIPTIONAL ACTIVATION IN MALIGNANT CELLS

Results

Conclusion