Propranolol inhibit tumor growth through reducing T cell exhaustion
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ABSTRACT:
PROVIDER: PRJNA862514 | ENA |
REPOSITORIES: ENA
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Project description:Recently, targeting or reinvigorating exhausted T cells have become the focus of cancer immunotherapy. Propranolol, a non-selection β1 and β2 adrenergic receptor blocker, or in combination with other drug, can inhibit the development of various tumors. Additionally, β2-adrenergic receptor (ADRB2) signaling suppresses the effector function of CD8+ T cell. However, whether propranolol plays an anti-tumor role by directly inhibiting T cell exhaustion remains unclear. In this study, we found that Propranolol significantly inhibited the development of AOM/DSS-induced colorectal cancer, and reduced the exhaustion of infiltrating T cell in colorectal cancer tissues. The anti-tumor effect of propranolol was further determined by CT26, B16F10, and MC38 subcutaneous tumor models in vivo. Cell viability analysis showed that Propranolol concentration below 40 μM had no effect on the viability of CT26 colorectal cancer cells. We also found that propranolol treatment did not inhibit the growth of tumors in BALB/c nude mice. The above results indicated that Propranolol relied on T cells to exert its anti-tumor effects. Bioinformatics analysis highlighted that ADRB2 was positive correlated with T cell exhaustion signature in colon adenocarcinoma, pancreatic adenocarcinoma, testicular germ cell tumors, and glioblastoma multiforme patients using the website of GEPIA. Accordingly, Propranolol directly inhibited T cells exhaustion, and increased IFN-γ secretion of CD4+ and CD8+ T cells in vitro. Collectively, propranolol plays anti-tumor role by directly inhibiting T cell exhaustion.
2023-04-28 | GSE209807 | GEO
Project description:The nonselective beta blocker, propranolol, which for decades has been used for treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we have investigated the anti-angiogenic properties of propranolol in the context of stimulating an anti-tumor immune response. We show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma tumors and improves the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol-treatment leads to an upregulation of PD-L1 on tumor-associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the efficacy of anti-CTLA4 therapy is significantly enhanced by the co-administration of propranolol. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially also in other cancers.
2022-03-01 | GSE174645 | GEO
Project description:We investigated the effect of a daily propranolol treatment (0.5mg/mL in the water bottle) on human melanoma xenografts development and the subsequent transcriptomic variations
2014-05-30 | E-MTAB-2404 | biostudies-arrayexpress
Project description:We investigated the effect of a daily propranolol treatment (0.5mg/mL in the water bottle) on human melanoma xenografts development and the subsequent transcriptomic variations
2014-05-30 | E-MTAB-2405 | biostudies-arrayexpress
Project description:We established a rat model of myocardial Infarction by performing a surgical operation of left anterior descending coronary artery occlusion under sterie conditions. Wistar rats were previously randomly divided into 4 groups: control, ischemia, ischemia-propranolol, and non-ischemia-propranolol. Our data suggested that propranolol could reverse many microRNAs with too high or too low expression in the ischemia group versus control group.
2009-11-19 | GSE18129 | GEO
Project description:Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. order to gain further insights in the mechanisms of action of R-propranolol in vivo, we subjected vehicle- and R-propranolol-treated tumors to RNAseq analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that choline metabolism was the pathway most affected by R-propranolol treatment. Consistent with this, the most highly regulated gene by R-propranolol treatment was Betaine-Homocysteine Methyl Transferase (Bhmt). Other genes that are involved in tumor suppressive activities such as Early Growth Response 1 (Egr1) and AP-1 subunit, which are both transcription factors implicated in tumor suppression. Egr1 regulates important tumor suppressors such as PTEN and p53, and upregulates tumor necrosis factor α (TNF-α). Fos, which has been known to be rearranged and expressed frequently in epithelioid hemangioma, was also upregulated in R-propranolol-treated samples. The genes identified in the RNAseq analysis pose as interesting targets for further investigations.
2019-10-04 | GSE138403 | GEO
Project description:We established a rat model of myocardial Infarction by performing a surgical operation of left anterior descending coronary artery occlusion under sterie conditions. Wistar rats were previously randomly divided into 4 groups: control, ischemia, ischemia-propranolol, and non-ischemia-propranolol. Our data suggested that propranolol could reverse many microRNAs with too high or too low expression in the ischemia group versus control group. Wistar rats were initially anesthetized with pentobarbital (40 mg/kg, i.v.), which were previously randomly divided into 4 groups: control, ischemia (MI), ischemia-propranolol (MI-PRO), and non-ischemia-propranolol (NMI-PRO). The rat model of MI was established by performing a surgical operation of left anterior descending coronary artery occlusion under sterie conditions. Successful occlusion was confirmed by an increase in the amplitude of R wave of lead I during the first few seconds of each occlusion and elevation of S-T segment of lead II, and a 20-30% decline in the arterial blood pressure compared to the pre-ischemic values mesured by a previously installed ECG recorder (BL 420, ChengDu TME Technology Co, Ltd, ChengDu, China). Propranolol was administrated 2 months before the experiment with daily oral doses of 50 mg/kg. Hearts were quickly isolated after the rats were sacrificed and the ischemic zone of the left ventricle was prepared for the miRNA microarray experiment. Control and NMI-PRO animals underwent open chest procedures without coronary artery occlusion.
2010-06-19 | E-GEOD-18129 | biostudies-arrayexpress
Project description:Propranolol, a non-selective β-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at non-toxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab, to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 downregulation trigger the same pathway, suggesting that AQP1 is a major driver of betablockers antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TC). Functional in vitro studies showed that AQP1-positive telocytes play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely at least in part to a cross talk between lesional vascular cells and stromal telocytes.
2021-01-25 | PXD021457 | Pride
Project description:Analysis of the effects of 4 hr and 24 hr propranolol treatment on gene expression of SVR mouse angiosarcoma cells. The hypothesis tested in the present study was that inhibiton of beta adrenergic receptor signaling could ablate the oncogenic properties of angiosarcoma cells. Results provide important information of the response of angiosarcoma cells to ablated beta adrenergic receptor signaling. The total RNA was obtained from mouse angiosarcoma cells cultured in monolayer at 0, 4, and 24 hrs of 50 micromolar propranolol treatment. Illumina microarrays were performed to determine the whole genome expression changes following treatment.
2013-06-01 | E-GEOD-42534 | biostudies-arrayexpress
Project description:One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion.
| S-EPMC3851591 | biostudies-literature