fig2

Figure 2. AhR activation not only increases CYP1B1 and the NAS/melatonin ratio but also oxidizes S1P lyase, leading to an increase in S1P. S1P is increased and ceramide decreased by the elevation in acid ceramidase in GBM/GSC. The increase in the S1P/ceramide ratio contributes to GBM/GSC survival, proliferation, migration and chemoresistance. The decrease in ceramide attenuates its suppression of 14-3-3, thereby potentiating the mitochondrial melatonergic pathway. Pineal melatonin is taken up by PEPT1/2 into mitochondria and induces Bmal1, which inhibits PDK, leading to disinhibition of the PDC, resulting in increased conversion of pyruvate to acetyl-CoA. Acetyl-CoA increases ATP from the TCA cycle and OXPHOS, as well as being a necessary co-substrate for AANAT and melatonergic pathway activation. Melatonin is intimately linked with the regulation of sirtuins and with antioxidant enzymes, including SOD2. Melatonin also inhibits the oxidized S1P lyase, leading to a decrease in S1P oncogenic effects. It is by such processes that variations in the mitochondrial melatonergic pathway are intimately linked to the intra- and extracellular processes in GBM/GSC and the cells of the tumour microenvironment. AANAT: aralkylamine N-acetyltransferase; AhR: aryl hydrocarbon receptor; ASMT: acetylserotonin methyltransferase; CYP: cytochrome P450; GBM: glioblastoma multiforme; GSC: glioblastoma stem-like cells; NAS: N-acetylserotonin; OXPHOS: oxidative phosphorylation; PDC: pyruvate dehydrogenase complex; PDK: pyruvate dehydrogenase kinase; PEPT: peptide transporter; S1P: sphingosine-1-phosphate; SOD: superoxide dismutase; TCA: tricarboxylic acid