Role of C5b-9 and RGC-32 in Cancer

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.

RGC-32 Regulates Generation of Reactive Astrocytes in Experimental Autoimmune Encephalomyelitis

“…Subsequent studies have shown that RGC-32 is an important cell cycle regulator, driving cell cycle progression in a number of cell types, such as smooth muscle cells and endothelial cells, by promoting the activity of CDC2/cyclin B complexes and Akt kinase (2,3). RGC-32 has also been shown to be involved in cell differentiation, tumorigenesis, and wound healing (4,5). Furthermore, RGC-32 has been found to be crucial for the TGFb-induced epithelial-to-mesenchymal transition in renal fibrosis and cancer metastasis (6)(7)(8).…”

Antibody‐mediated complement activation in pathology and protection

“…In chronic inflammation, anaphylatoxins—particularly C5a—can promote a protumor microenvironment through a variety of mechanisms, including chemotactic recruitment of tissue‐infiltrating myeloid cells that are stimulated to secrete immunosuppressive molecules, thereby sustaining a protumor microenvironment 58 . In addition, sublytic terminal complement complexes can have oncogenic effects, including cell cycle modulation and resistance to apoptosis and complement 59 . Mechanisms of tumor cell complement evasion include antigenic modulation 60 and overexpression of complement regulatory proteins, of which CD59 (membrane attack complex‐inhibitory protein, or protectin) inhibits C9 polymerization and can induce internalization of affected areas of membrane in order to escape membrane attack complex lysis 61 .…”

Targeting the Complement Pathway in Malignant Glioma Microenvironments

“…Under the action of these proteins, the MAC cannot form a complete permeable pore across the cell membrane and becomes a partially dissolved form, sublytic C5b-9(sC5b-9), which is embedded in the membrane. sC5b-9 can activate multiple signaling pathways, including PI3K-Akt, ERK, JAK1-STAT3, and NF-κB, and regulates tumor cell growth in a G protein-dependent manner ( Vlaicu et al, 2019 ). sC5b-9 is highly expressed in lymphomas and oral squamous cell carcinoma cells ( Niculescu et al, 1997 ; Pilzer and Fishelson, 2005 ; Gallenkamp et al, 2018 ).…”

“…RGC32 is involved in cell differentiation, cell cycle regulation, and immune regulation under physiological conditions ( Badea et al, 1998 ; Vlaicu et al, 2008 ). In tumors, the expression and function of RGC32 are disease-dependent ( Vlaicu et al, 2019 ). RGC32 is highly expressed in colon cancer, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, and lymphoma.…”

“…et al, 2017 ). However, RGC32 is downregulated in glioblastoma, astrocytoma, multiple myeloma, and adrenocortical tumors and acts as a tumor suppressor instead ( Vlaicu et al, 2019 ). Interestingly, RGC32 can be both upregulated and downregulated in non-small-cell lung cancer, and its specific expression and function still need more in-depth revelation in the context of this disease ( Kim D.S.…”