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.
Highlights
Recent work on the pathophysiology of the severe acute respiratory syndromecoronavirus (SARS-CoV)-2 in the COVID-19 pandemic has highlighted the co-ordinating role of the aryl hydrocarbon receptor (AhR), including in the suppression of CD8+ T cell and natural killer (NK) cell cytotoxicity [1]
This is another cancer stem-like cells (CSC) survival cycle that is increased by the O-GlcNAcylation of YY1, which concurrently enhances immunosuppression via transforming growth factor (TGF)-β1 effects, including via the induction of myeloid-derived suppressor cells (MDSC) adenosine leading to A2A receptor (A2Ar) activation-driven ‘exhaustion’ in NK cells and CD8+ T cells [108]
Many of the factors significantly associated with tumour progression and immunosuppression, such as YY1, SIRT1/3, GSK3β, STAT, IDO and the AhR can have their influence and interactions more plausibly integrated by their impacts on metabolism, acetyl-CoA and the melatonergic pathway within the cells of the tumour microenvironment
Summary
Recent work on the pathophysiology of the severe acute respiratory syndromecoronavirus (SARS-CoV)-2 in the COVID-19 pandemic has highlighted the co-ordinating role of the aryl hydrocarbon receptor (AhR), including in the suppression of CD8+ T cell and natural killer (NK) cell cytotoxicity [1]. Other pathways induce an ‘exhausted’ phenotype, including cancer cell release of transforming growth factor (TGF)-β, the activation of the adenosine A2A receptor (A2Ar) and the induction of the cyclooxygenase (COX)2-prostaglandin (PG)E2 path leading to the activation of the PGE2 receptor, (EP). It is proposed that the maintained production and availability of acetyl-CoA, an indicant of OXPHOS, is a determinant of glycolysis upregulation, with acetyl-CoA acting to regulate the many factors and intracellular pathways contributing to ‘exhaustion’, including TGF-β, adenosine A2Ar activation and AhR/COX2/PGE2/EP4 activation, as well as the effects of obesity and type II diabetes on cancer risk, which are partly driven by raised leptin levels priming cytolytic cells [7]. Treatment implications and future research are indicated, including a role for racial discrimination stress in contributing to the increased severity/fatality of a range of cancers, as seen in African-Americans versus European-Americans, via an increase in pro-inflammatory cytokines and indoleamine 2,3-dioxygenase (IDO) induction, leading to kynurenine activation of the AhR
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