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.

Keywords: C5b-9; RGC-32; apoptosis; cancer; cell proliferation.

Figure 1

Sublytic C5b-9 promotes tumor growth and survival by activating several signaling pathways. The assembly of C5b-9 complexes in the cellular membrane activates the heterotrimeric G proteins of the G_i subtype (38). The β-γ complex is thought to activate several intracellular signaling cascades, including: a) phosphatidylinositol 3 kinase (PI3K)-Akt signaling pathway. Activated Akt phosphorylates and inactivates the pro-apoptotic factors Bad and Bim, resulting in the release of the pro-survival factors Bcl-2 and Bcl-xL, which migrate into the mitochondrial matrix and inhibit the release of cytochrome C (cyto C), thus inhibiting apoptosis. Akt also phosphorylates the transcription factor FOXO1, promoting its nuclear exclusion and inhibiting FOXO1-mediated transcription of pro-apoptotic factors (6, 39); b) Ras-Raf-MEK1-ERK1 signaling pathway, resulting in the activation of transcription factors associated with cell proliferation (AP-1 and Elk1); c) JAK1-STAT3 signaling pathway, leading to the formation of STAT3 homodimers and their nuclear translocation (, –41). Another recently described mechanism which may account for the activation of genes associated with cell proliferation is the activation of the non-canonical NF-κB signaling pathway by the endosomal C5b-9 complexes, involving the NF-κB-inducing kinase (NIK) (42). An important consequence of C5b-9 assembly is the increased concentration of cytosolic calcium ions (Ca²⁺), either through direct entry of extracellular Ca²⁺ or by endoplasmic reticulum release triggered by intracellular second messengers (43) (not shown).

Figure 2

Molecular mechanisms underlying the role of RGC-32 in oncogenesis. RGC-32 can act both as a tumor suppressor (red inhibitory lines) and a tumor promoter (blue arrows) in a variety of cancers by activating a plethora of molecular pathways. RGC-32 plays an important role in: (a) promoting the TGF-β-induced epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells lose their adhesiveness and gain myofibroblast-like phenotypes, inducing metastasis and cancer progression (80, 91, 92); (b) epigenetic modifications, by inducing histone deacetylases (HDACs), which in turn deacetylate various histone targets such as H2B at lysine 5 (H2BK5), H2BK15, H3K9, and H4K8 and indirectly promote the tri-methylation of H3K27. This in turn may result in transcriptional repression of genes associated with cancer progression (77); (c) cell cycle regulation, in which RGC-32 can promote mitosis by enhancing the activity of kinases crucial for cell cycle progression (93), or induce cell cycle arrest in a p53-dependent manner (88); (d) inhibition of angiogenesis, in which it may behave as a negative feedback regulator of hypoxia-induced signaling pathways (94). The involvement of RGC-32 in these processes might explain its apparent dual role as a tumor suppressor/promoter in the same type of tumor, such as colon cancer.