Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

Abstract

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven ‘backward’ conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

“…Melatonin, to the authors knowledge, is the first endogenously produced molecule that has been shown to be capable of redirecting pyruvate metabolism away from the fermentation pathway and into the mitochondria for the support of the TCA cycle and OXPHOS [23,125]. Thus, the well-documented actions of melatonin on cancer progression [15,17,155,225] may be related to its ability to inhibit elevated cytosolic glycolysis of these cells [226]. Since this may be the case, it is also possible that melatonin's efficiency in reducing the severity of other diseased cells that display this altered metabolism (see Table 1) may likewise be related to its ability to limit pyruvate conversion to lactate and to redirect it into the mitochondria, thereby normalizing the metabolism of this organelle and rendering the cells less-diseased/pathological [20].…”

Melatonin and the Programming of Stem Cells

“…Melatonin has been shown to modulate the cargo composition of exosomes and, thereby, the regulatory potential of these vesicles [3,29,220,221]. This was impressively confirmed for MSCs, as recently summarized with a focus on tumor biology [222]. Importantly, MSCs were found to release relatively high amounts of exosomes [223].…”

Untargeted metabolomics profiling in a mouse model of lung cancer treated with thermal ablation

“…For instance, overexpressed fatty acyls and glycerophospholipids, such as eicosanoids, lysophosphatidylserine, and phosphatidyl choline, participate in cell signaling of inflammation and immune responses [ 25 , 26 ]. Downregulated metabolites, such as vitamin A [ 27 ] (prenol lipids), N-acetylsphingosine, N-acetylserotonin, and O-arachidonoyl ethanolamine (fatty acyls), could increase the survival likelihood of tumor, proliferation of cancer cells, and immune suppression [ 28 ]. The enriched pathways in both ablation groups, including steroid hormone biosynthesis and tryptophan metabolism, also contributed to tumor progression and immune evasion ( Figure 4 ).…”