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

George Anderson, Russel J Reiter

Research output: Contribution to journalReview article

7 Scopus citations

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.

Original languageEnglish (US)
JournalInternational Journal of Tryptophan Research
Volume12
DOIs
StatePublished - Jun 1 2019

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Keywords

  • aryl hydrocarbon receptor
  • glioblastoma
  • glioblastoma stem-like cell
  • kynurenine
  • melatonin
  • mitochondria
  • N-acetylserotonin
  • sirtuins
  • treatment
  • tryptophan 2,3-dioxygenase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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