TY - JOUR
T1 - Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
AU - Fernandez-Gil, Beatriz I.
AU - Otamendi-Lopez, Andrea
AU - Bechtle, Alexandra
AU - Vazquez-Ramos, Carla A.
AU - Qosja, Neda
AU - Suarez-Meade, Paola
AU - Sarabia-Estrada, Rachel
AU - Jentoft, Mark E.
AU - Guerrero-Cázares, Hugo
AU - Escames, Germaine
AU - Schiapparelli, Paula
AU - Quiñones-Hinojosa, Alfredo
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - GBM
KW - LDHA
KW - MCT4
KW - OXPHOS
KW - ROS
KW - cancer metabolism
KW - glycolysis
KW - intracellular acidity
KW - lactate
UR - http://www.scopus.com/inward/record.url?scp=85141641036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85141641036&partnerID=8YFLogxK
U2 - 10.3390/cells11213467
DO - 10.3390/cells11213467
M3 - Article
C2 - 36359862
AN - SCOPUS:85141641036
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 21
M1 - 3467
ER -