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

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.

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches

“…In particular, hyperglycemia plays a pivotal role in the generation of glycated adducts called advanced glycation end products (AGEs). AGEs result from non-enzymatic glycation of proteins, nucleic acids, and lipids chronically exposed to elevated concentrations of glucose [ 106 ]. The Receptor for Advanced Glycation End Products (RAGE) is a transmembrane protein belonging to the immunoglobulin superfamily.…”

Glyoxalase System in Breast and Ovarian Cancers: Role of MEK/ERK/SMAD1 Pathway

“…This complicated system plays a crucial role in detoxifying methylglyoxal (MGO), a compound produced as a byproduct of glycolysis [34]. Elevated levels of MGO, often associated with increased glycolytic activity in cancer cells, contribute to the formation of advanced glycation end-products (AGEs) and oxidative stress, fostering a microenvironment conducive to tumorigenesis [38]. The glyoxalase system comprises two enzymes: S-lactoylglutathione lyase, referred to as GLO1 (EC 4.4.1.5), and hydroxyacylglutathione hydrolase, known as GLO2 (EC 3.2.1.6).…”