Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma.
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ABSTRACT:
PROVIDER: PRJNA789912 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR17263824.fastq.gz | Fastqsanger.gz | |||
| SRR17263825.fastq.gz | Fastqsanger.gz | |||
| SRR17263826.fastq.gz | Fastqsanger.gz | |||
| SRR17263827.fastq.gz | Fastqsanger.gz | |||
| SRR17263829.fastq.gz | Fastqsanger.gz |
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Project description: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.
2022-05-31 | GSE191165 | GEO
Project description:BackgroundMedulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis.MethodsMedulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production.FindingsLow concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages.InterpretationThese data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours.FundingThis study was funded by institutional grants and charities.
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Project description:Glucose-stimulated insulin secretion (GSIS) is suppressed through α-adrenergic receptor stimulation by catecholamines, epinephrine and norepinephrine, in pancreatic β-cells. Previous work has elucidated a bevy of adrenergic regulatory mechanisms beyond traditional Gi-coupled signaling including regulation of ion channels and interactions with exocytotic machinery. Glucose oxidation may also be an important site for adrenergic regulation of GSIS, but the link between epinephrine and glucose oxidation in β-cells is undefined. Here, we evaluate whether adrenergic stimulation decreases oxidative metabolism in β cells. Oxygen consumption rates were determined for Min6 and isolated rat islets in 20mM glucose complete media, then epinephrine was added at either 0 nM (vehicle control) or 100nM, followed by 10uM yohimbine (a selective Adrα2A antagonist). To identify glucose oxidation as the primary metabolic pathway affected by epinephrine, oxidation of 14C(U)-labeled glucose was determined in Min6 cells with epinephrine or vehicle. Oxygen consumption and glucose oxidation experiments were conducted in the presence of cAMP and insulin secretion blockers, respectively. Proteomics was performed on Min6 cells exposed to epinephrine for 4 hours and compared to controls. Epinephrine, but not vehicle, reduced (P<0.01) oxygen consumption rates in rat islets and Min6 cells to 64 ± 6% and 65 ± 1% of baseline, respectively, and yohimbine restored oxygen consumption to rates not different from baseline. In Min6 cells incubated with epinephrine rates of 14C glucose oxidation were reduced (P<0.01) 66 ± 4% compared to vehicle controls. These results demonstrate that acute epinephrine exposure suppresses glucose oxidation in β cells via the specific adrenergic receptor, Adrα2A, and indicate a new role for adrenergic regulation in GSIS.
2019-11-08 | PXD006330 | Pride
Project description:Rationale: The molecular underpinnings of heart failure with reduced ejection fraction (HFrEF) involves a complex remodeling of the contractile, metabolic and electrical functions. Current pharmacotherapy for patients presenting HFrEF includes combination of angiotensin-converting enzyme inhibitors (ACEi) and β-adrenergic receptor blockers (β-AR blockers). Yet, a knowledge gap exists regarding the molecular changes accompanying such treatment. Objective: The present study takes an omics approach to study protein and phosphorylation signaling derangement in HFrEF and to define the global changes resulting from treatment with β-AR blocker (metoprolol) and ACE inhibitor (enalapril) in control- and HFrEF hearts.
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Project description:We screened RNAseq results from RAW 264.7 macrophages for previous empirically-defined M2 genes in the whole transcriptome that followed the Arg1 pattern of up-regulation by β-adrenergic-signaling with inhibition by Cebpb gene knockdown. We also screened RAW 264.7 macrophages for empirically-defined M1 genes that exhibited the orthogonal pattern of Arg1 regulation (i.e., down-regulation by β-adrenergic signaling, with rescue of this effect by Cebpb knockdown).
2019-05-08 | GSE119707 | GEO
Project description:Experiment designed to identify differences in gene expression profile in white adipose tissue upon stimulation by beta 3 adrenergic receptor agonist. This series compares 2 groups of C57BL/6J acutely treated with CL-316,243 or Saline for 3 hours.
2010-06-11 | E-GEOD-2674 | biostudies-arrayexpress
Project description:The activity of bone marrow hematopoeitic cells is tightly controlled by neurogenic innervations. As bone marrow cells mainly receive innervation from beta-3 adrenergic receptor, here we investigated the impact of beta3-adrenergic innervation on bone marrow cell transcriptome alterations. We sorted hematopoetic stem cells (HSCs) from wild type mice (control group) or Adrb3-/- mice (devoid of beta3-adrenergic receptor). Thereafter, Nanostring assessment was performed to compare the transcriptome alterations.
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Project description:GDF15 links beta-adrenergic induced lipolysis with anxiety
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Project description:CD8+ T cells are essential components of the body’s immune reaction against viral infections and tumors, capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion. Exhausted CD8+ T cells are characterized by expression of multiple inhibitory receptors, like PD-1 and TIM3 and reduced capacity to secrete cytokines, and are commonly found in chronic viral infections, like HIV and HBV, as well as in immunosuppressive tumor microenvironments (TME). Cancer and chronic infection also place considerable stress on tissue architecture and function, and while it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a previously undescribed link between the stress-associated catecholamines adrenaline and noradrenaline and the development of T cell exhaustion through the β1-adrenergic receptor, ADRB1. We identify that exhausted CD8+ T cells express higher levels of ADRB1, and exposure of ADRB1-expressing T cells to catecholamines suppresses cytokine production and impairs T cell proliferation. Genetic or pharmacological ablation of β-adrenergic signaling via ADRB1 reduces development of T cell exhaustion in a chronic infection model and improves cytotoxic functions in tumor-infiltrating lymphocytes (TILs) when combined with immune checkpoint blockade (ICB) therapy in a melanoma model. Extending these findings to an ICB-resistant tumor model of murine pancreatic cancer, we show that beta-blockers and ICB synergize to enhance and reprogram T cell responses. Given that malignant disease is associated with increased systemic catecholamine levels in patients and therapeutic stress reduction improves survival in cancer patients, our results demonstrate a potential link between systemic stress, tumor innervation and immune responses. Our findings show that β-adrenergic signaling constitutes a novel targetable immune checkpoint in CD8+ T cells to rejuvenate antitumor functions. More broadly, our results support further clinical investigation into the application of beta-blockers, which are clinically safe and widely prescribed, as an immunomodulating agent for cancer immunotherapy.
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Project description:Colon and rectal cancer is the second most prevalent malignant disease in the western world, causing significant morbidity, mortality, and healthcare sources use. Treating colon and rectal cancer with curative intent generally includes resection of the primary tumor. Despite its crucial role, surgery by itself induce physiological changes resulting in significant immune depression and other physiological perturbations, which may in turn play a significant role in the initiation of new metastases and the progression of pre-existing dormant metastases. The aim of this study is to assess the use of perioperative medical intervention using a combination of a β-adrenergic blocker (Propranolol) and a COX2 inhibitor (Etodolac), in order to attenuate the surgically induced immunosuppression and other physiological perturbations, aiming to reduce the rate of tumor recurrence and distant metastatic disease.
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