Role and Mechanisms of RAGE-Ligand Complexes and RAGE-Inhibitors in Cancer Progression

Abstract

Interactions of the receptor for advanced glycation end product (RAGE) and its ligands in the context of their role in diabetes mellitus, inflammation, and carcinogenesis have been extensively investigated. This review focuses on the role of RAGE-ligands and anti-RAGE drugs capable of controlling cancer progression. Different studies have demonstrated interaction of RAGE with a diverse range of acidic (negatively charged) ligands such as advanced glycation end products (AGEs), high-mobility group box1 (HMGB1), and S100s, and their importance to cancer progression. Some RAGE-ligands displayed effects on anti- and pro-apoptotic proteins through upregulation of the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF-κB) pathways, while downregulating p53 in cancer progression. In addition, RAGE may undergo ligand-driven multimodal dimerization or oligomerization mediated through self-association of some of its subunits. We conclude our review by proposing possible future lines of study that could result in control of cancer progression through RAGE inhibition.

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

“…RAGE is a 45-kDa transmembrane receptor that belongs to the immunoglobulin superfamily, and widely expressed in various types of cells, such as immune cells (macrophages, neutrophils, and mast cells), endothelial cells, and neurons [ 67 ]. Accumulating evidence reveals that RAGE contributes to the pathogenesis of many diseases, including diabetic complications, Alzheimer′s disease, cardiovascular diseases, arthritis, and cancer [ 15 , 67 , 68 , 69 ]. It is of note that RAGE is overexpressed in the vast majority of cancer cells [ 68 ].…”

“…RAGE was originally identified as a receptor for advanced glycation end products (AGEs), but is now known to respond to at-HMGB1, S100 proteins, and amyloid β [ 15 ]. RAGE, when stimulated, activates cell signals including mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) ( Figure 1 C) [ 68 , 69 ]. A number of studies demonstrate that RAGE is required for HMGB1-induced inflammation [ 70 ], pain [ 16 , 19 , 30 , 32 ], cell migration [ 71 ], neuritogenesis [ 72 ], autophagy [ 73 ], and proliferation [ 74 , 75 ].…”

The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers

“…For instance, the RAGE–ligand interactions could effectively induce antiapoptotic and proapoptotic protein expression through the upregulation of PI3K/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF-κB) pathways. However, these ligand interactions induce the downregulation of p53 expression, consequently inflicting cancer progression [ 13 ]. Furthermore, RAGE–ligand interactions can form multimodal dimerization, which eventually induces cancer progression; hence, the inhibition of RAGEs could effectively control cancer progression [ 13 ].…”

“…However, these ligand interactions induce the downregulation of p53 expression, consequently inflicting cancer progression [ 13 ]. Furthermore, RAGE–ligand interactions can form multimodal dimerization, which eventually induces cancer progression; hence, the inhibition of RAGEs could effectively control cancer progression [ 13 ]. Clinical studies have delineated that determining the RAGE levels in body fluids could be used as novel biomarkers for several cancers, viz., lung cancer [ 14 ], breast cancer [ 15 ], prostate cancer [ 16 ], and colorectal cancer [ 17 , 18 ].…”

“…Recent studies have demonstrated that the targeted inhibition of RAGE-signaling cascades using papaverine, ethyl pyruvate, hispidin, duloxetine, etc. could retard gliomas and sarcomas [ 13 , 19 , 20 ].…”