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Review
. 2023;4(5):812-849.
doi: 10.37349/etat.2023.00170. Epub 2023 Sep 28.

AGEs and RAGE: metabolic and molecular signatures of the glycation-inflammation axis in malignant or metastatic cancers

Gowri Palanissami  1 , Solomon F D Paul  1
Affiliations
Review

AGEs and RAGE: metabolic and molecular signatures of the glycation-inflammation axis in malignant or metastatic cancers

Gowri Palanissami et al. Explor Target Antitumor Ther. 2023.

Abstract

From attributing mutations to cancers with the advent of cutting-edge genetic technology in recent decades, to re-searching the age-old theory of intrinsic metabolic shift of cancers (Warburg's glycolysis), the quest for a precise panacea for mainly the metastatic cancers, remains incessant. This review delineates the advanced glycation end product (AGE)-receptor for AGE (RAGE) pathway driven intricate oncogenic cues, budding from the metabolic (glycolytic) reliance of tumour cells, branching into metastatic emergence of malignancies. Strong AGE-RAGE concomitance in metastasis, chemo-resistance and cancer resurgence adversely incite disease progression and patient mortality. At the conjunction of metabolic and metastatic shift of cancers, are the "glycolytically" generated AGEs and AGE-activated RAGE, instigating aberrant molecular pathways, culminating in aggressive malignancies. AGEs as by-products of metabolic insurgence, modify the metabolome, epigenome and microbiome, besides coercing the inter-, intra- and extra-cellular micro-milieu conducive for oncogenic events like epithelial-mesenchymal transition (EMT). AGE-RAGE synergistically elicit ATP surge for surplus energy, autophagy for apoptotic evasion and chemo-resistance, insulin-like growth factor 1 (IGF-1) for meta-inflammation and angiogenesis, high mobility group box-1 (HMGB1) for immune tolerance, S100 proteins for metastasis, and p53 protein attenuation for tumour suppression. AGEs are pronouncedly reported in invasive forms of breast, prostate, colon and pancreatic cancers, higher in patients with cancer than healthy counterparts, and higher in advanced stage than localized phase. Hence, the investigation of person-specific presence of AGEs, soluble RAGE and AGE-activated RAGE can be advocated as impending bio-markers for diagnostic, prognostic and therapeutic purposes, to predict cancer risk in patients with diabetes, obesity, metabolic syndrome as well as general population, to monitor prognosis and metastasis in patients with cancer, and to reckon complications in cancer survivors. Furthermore, clinical reports of exogenous (dietary) and endogenous (internally formed) AGEs in cancer patients, and contemporary clinical trials involving AGE-RAGE axis in cancer are underlined with theranostic implications.

Keywords: AGEs; RAGE; S100; cancer; epigenome; glycation; high mobility group box-1; microbiome.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
AGE-RAGE pathway driven intricate molecular cues in cancer cells, giving rise to metastasis and chemo-resistance. Oncogenic cues triggered by metabolic imprint of AGEs and up-regulated glycolytic reactions, under conditions of hyperglycemia and hypoxia (also Warburg’s aerobic glycolysis), respectively, with the mutagenic exposure of exogenous (dietary) and endogenous AGEs, culminating in activated RAGE-driven metabolic, apoptosis to autophagy and metastatic switch, characteristic of malignant transformation and capable of eliciting chemo-resistance. Multi-stage transformation of metabolic switch of cancer cells to metastatic surge, driven by AGEs and RAGE-mediated aberrant molecular cues, result in the concurrent generation of multiple hallmarks of cancer, from altered mitochondrial bio-energetics to sustained proliferative signals, redox imbalance, evasion of tumour suppression, apoptotic evasion, inflammation, angiogenesis, invasion and metastasis. HIF-1α: hypoxia-inducible factor 1α; GLO-1: glyoxalase-1; NOX-2: reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme-2; MCT-4: monocarboxylate transporter-4; GLUT-1: glucose transporter-1; MMP1: matrix metalloproteinase 1; CXCR4: C-X-C chemokine receptor 4; TGF-β: transforming growth factor β; LC-3: microtubule-associated protein light chain 3; VEGF: vascular endothelial growth factor; SP-1: stimulator protein-1; Bcl-2: B cell lymphoma protein-2; G1: first gap or growth phase; M: mitosis phase; S: synthesis phase
Figure 2
Figure 2
AGE-RAGE signalling cascade incited in different cellular components of tumour-micro milieu facilitating malignant transformation. Oncogenic molecular cues in cancer cells, and in stromal component, comprising of CAFs, MDSCs, TAMs and other tumour-supporting immune cells, all bound together by ECM, constituting the tumour micro-environment (TME). The molecular interplay between cancer cells and associated stromal cells via AGE-RAGE axis generates a TME conducive for the elicitation of malignant features of cancer, via incitation of cell proliferation and survival, evasion of apoptosis and tumour suppression, autophagy induction and chemo-resistance, tumour-promoting inflammation and immune suppression, ultimately leading to ECM remodelling, invasion and metastasis. IκB: NF-κB inhibitor; GSK-3β: glycogen synthase kinase 3β; c-Fos: FBJ murine osteosarcoma viral oncogene homolog (AP-1 transcription factor subunit); MDSC: myeloid-derived suppressor cell; TAM: tumor associated macrophage; P: phosphorylation
Figure 3
Figure 3
AGEs-mediated oncogenic alterations in intestinal micro-milieu and gut microbiome. Accretion of AGEs, both dietary/exogenous and endogenous AGEs, incite multiple cellular and molecular events, including protein fermentation, glycation, inflammation, colonic permeability, gut barrier dysfunction, pro-inflammatory cytokines/ligands by AGEs-RAGE-ROS-NF-κB signalling, augmented LPS circulation levels, gut microbial dysbiosis, all leading to the onset of glycation- and inflammation-induced cancers, both local and systemic, and ultimately malignant transformation. Synbiotics and natural polyphenols can be used in combination to curb the side effects of conventional chemotherapy, and those with AGE/RAGE inhibitory potential can be exploited to synergize cancer treatment. LPS: lipopolysaccharide
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