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Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma.

ABSTRACT: Our study showed that propranolol, carvedilol and nebivolol inhibited medulloblastoma cell proliferation and invasion by affecting energy metabolism pathways (OXPHOS and glycolysis) and by triggering a metabolic catastrophe that deprived tumor cells of their adaptive bioenergetics capacities. To better understand the importance of bioenergetics in response to treatment, we generated β-blocker-resistant ONS-76 cells by exposing them to increasing concentrations of propranolol, carvedilol or nebivolol for 16 weeks. The resulting cell lines i.e., ONS-76 RP, ONS-76 RC and ONS-76 RN, displayed a higher mitochondrial OCR and ATP production than the sensitive parental ONS-76 WT cells. By qRT-PCR, we showed that the expression of β-blockers canonical targets (β-ARs) was not altered in these resistant cells. Sequencing of total RNA from the four meduloblastoma cell models further indicated that cell resistance could not be explained by the down-regulation of key proteins of the β-AR downstream signaling, including the adenylate cyclase or their transcriptional targets. Our data also showed that the efficacy of propranolol, carvedilol and nebivolol was not impacted by β-AR silencing, further supporting the idea that β-blockers trigger an alternative signaling pathway in medulloblastoma cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE191165 | GEO | 2022/05/31

REPOSITORIES: GEO

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Project description:Propranolol is a beta-adrenergic receptor antagonist (Î²-blocker) that has been detected in United States wastewater effluents at concentrations ranging from 0.026 to 1.90 Âµg/l. In mammals, there is evidence that Î²-blockers can cause sexual dysfunction, and alter serotonergic pathways which may impact reproductive behavior but little is known about the effects on fish behavior. The present study tested the effects of propranolol on fecundity and on reproductive behavior of the fathead minnow, Pimephales promelas, a fish that exhibits male parental care. Sexually mature fathead minnows were housed at a ratio of one male and two females per tank and exposed to nominal concentrations of 0, 0.1, 1, 10 Âµg/l for 21 days. Measured concentrations (Â±SD) of propranolol were 0.05Â±0.02, 0.88Â±0.34 and 4.11Â±1.19 Âµg/l. There were no statistically significant differences in fecundity, fertilization rate, hatchability and time to hatch. Propranolol exposure was not associated with a change in nest rubbing behavior, time spent in the nest or approaching the females. There was a significant difference in the number of visits to the nest with males receiving low and medium propranolol treatments. The microarray analysis showed that there were 335 genes up-regulated and 400 genes down-regulated in the brain after exposure to the highest dose of propranolol. Among those genes, myoglobin and calsequestrin transcripts (fold change=10.84 and 5.49, respectively) were highly up-regulated. Ontological analyses indicated changes in genes involved in calcium ion transport, transcription, proteolysis and apoptosis/anti-apoptosis. The results showed that exposure to propranolol at concentrations as high as 4.11 Âµg/l did not significantly impact reproductive behavior or spawning abilities of fathead minnow but did alter the regulation of genes within the brain of fish. Effects of propanolol exposure were investigated in the brain of adult male fathead minnow exposed to 10 Âµg/L of propanolol or a solvent control solution (0.01% ethanol). For each treatment, the brain of four different fish were analyzed.

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Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma.

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