Glioblastoma: Role of Mitochondria N-acetylserotonin/Melatonin Ratio in Mediating Effects of miR-451 and Aryl Hydrocarbon Receptor and in Coordinating Wider Biochemical Changes

Abstract

A wide array of different factors and processes have been linked to the biochemical underpinnings of glioblastoma multiforme (GBM) and glioblastoma stem cells (GSC), with no clear framework in which these may be integrated. Consequently, treatment of GBM/GSC is generally regarded as very poor. This article provides a framework that is based on alterations in the regulation of the melatonergic pathways within mitochondria of GBM/GSC. It is proposed that the presence of high levels of mitochondria-synthesized melatonin is toxic to GBM/GSC, with a number of processes in GBM/GSC acting to limit melatonin’s synthesis in mitochondria. One such factor is the aryl hydrocarbon receptor, which increases cytochrome P450 (CYP)1b1 in mitochondria, leading to the ‘backward’ conversion of melatonin to N -acetylserotonin (NAS). N -acetylserotonin has some similar, but some important differential effects compared with melatonin, including its activation of the tyrosine receptor kinase B (TrkB) receptor. TrkB activation is important to GBM/GSC survival and proliferation. A plethora of significant, but previously disparate, data on GBM/GSC can then be integrated within this framework, including miR-451, AMP-activated protein kinase (AMPK)/mTOR, 14-3-3 proteins, sirtuins, tryptophan 2,3-dioxygenase, and the kynurenine pathways. Such a conceptualization provides a framework for the development of more effective treatment for this poorly managed condition.

Melatonin’s Antineoplastic Potential Against Glioblastoma

“…In the hopes of blocking tumor growth, Franco et al [35] studied the effects of 3 mM melatonin on human GBM cells and observed a reduced expression of mitochondrial transcription factor A (TFAM), which is an essential protein that maintains mitochondrial DNA (mtDNA) integrity [65,66]. Moreover, melatonin selectively induced a surprisingly concentration-dependent increase in ROS production and delayed cell-cycle progression in GBM cancer cells as compared to the control group [35], while the presence of high levels of mitochondria-synthesized melatonin appears to be toxic for GBM and GSCs [67]. This effect of melatonin on ROS production may be due to the altered expression of respiratory chain genes, which could depend on the activity of the transcription factors TFAM, TFB1M, and TFB2M [35].…”

Left Ventricular Hypertrophy: Roles of Mitochondria CYP1B1 and Melatonergic Pathways in Co-Ordinating Wider Pathophysiology

“…Many of the changes associated with LVH are also evident in proliferative conditions, such as endometriosis and a wide array of cancers [8,9]. Recent works suggest that alterations in mitochondria functioning, particularly the regulation of the melatonergic pathways, may be a core aspect of how changes in mitochondria drive the co-ordinated pathophysiological processes underpinning these diverse medical disorders [8,9]. The current article reviews how aryl hydrocarbon receptor (AhR)-induced cytochrome P450 (CYP)1B1 suppresses mitochondria melatonin production, thereby initiating the co-ordinated cellular changes evident in LVH.…”

The effects of melatonin on signaling pathways and molecules involved in glioma

“…High levels of melatonin synthesis in mitochondria are very toxic to GBM/GSC; hence, some processes in GBM/GSC limit mitochondria‐synthesized melatonin. For example, aryl hydrocarbon receptor increases cytochrome P450 (CYP)1b1 in mitochondria which leads to the ‘backward’ conversion of melatonin to N‐acetylserotonin (NAS) .…”