Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
Metadata
Show full item recordEditorial
MDPI
Materia
Intracellular acidity Cancer metabolism Lactate MCT4 ROS LDHA GBM OXPHOS Glycolysis
Date
2022-11-02Referencia bibliográfica
Fernandez-Gil, B.I.; Otamendi-Lopez, A.; Bechtle, A.; Vazquez-Ramos, C.A.; Qosja, N.; Suarez-Meade, P.; Sarabia-Estrada, R.; Jentoft, M.E.; Guerrero-Cázares, H.; Escames, G.; et al. Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma. Cells 2022, 11, 3467. [https://doi.org/10.3390/cells11213467]
Sponsorship
Distinguished Mayo Clinic Investigator Award (A.Q.-H.); William J. and Charles H. Mayo Professor (A.Q.-H.); Uihlein Neuro-oncology Research Fund (A.Q.-H.); R01CA200399 (A.Q.-H.)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.