Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma

Beatriz I. Fernandez-Gil, Andrea Otamendi-Lopez, Alexandra Bechtle, Carla A. Vazquez-Ramos, Neda Qosja, Paola Suarez-Meade, Rachel Sarabia-Estrada, Mark E. Jentoft, Hugo Guerrero-Cázares, Germaine Escames, Paula Schiapparelli, Alfredo Quiñones-Hinojosa

Research output: Contribution to journalArticlepeer-review

Abstract

Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin’s functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin’s cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.

Original languageEnglish (US)
Article number3467
JournalCells
Volume11
Issue number21
DOIs
StatePublished - Nov 2022

Keywords

  • GBM
  • LDHA
  • MCT4
  • OXPHOS
  • ROS
  • cancer metabolism
  • glycolysis
  • intracellular acidity
  • lactate

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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