Single-cell RNA-seq profiles of murine sarcoma tumors with vehicle and digoxin treatments
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ABSTRACT:
PROVIDER: PRJNA629842 | ENA |
REPOSITORIES: ENA
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Project description:Myocardial ischemia-reperfusion injury (MIRI) is a major threat to heart functional integrity and pharmacological means to achieve cardioprotection are sorely needed. The sequential hypoxic/normoxic status of the cardiac tissue triggers life-threatening damages through the activation of multiple intra-cellular pathways. Heart tolerance to MIRI varies according to a day-night cycle and is regulated by components of the molecular clock such as the transcriptional repressor and nuclear receptor REV-ERBα. Timed REV-ERBα antagonism alleviates sensitivity to myocardial infarction in mice. Here we show that timed administration of digoxin is cardioprotective by triggering REV-ERBα protein degradation and involves the anti-apoptotic factor p21. Kinomics and transcriptomic assays revealed that in several cardiomyocyte cellular models, digoxin and other cardiotonic steroids induced multiple signaling pathways at subinotropic doses. Pharmacological inhibition and knockdown approaches revealed that inhibition of phosphatidylinositol 3- and of Src tyrosine-kinase partially alleviated digoxin-induced REV-ERBα degradation, which was fully prevented upon proteasome inhibition. REV44 ERBα is increasingly ubiquitinylated in digoxin-treated cells, and its degradation depends on its ability to bind its natural ligand, heme. In normal conditions, the proteasomal degradation of REV-ERBα is controlled by several known (HUWE1, FXW7, SIAH2) or novel (CBL, UBE4B) E3 ubiquitin ligases. Only SIAH2 together with the proteasome subunit PSMB5 contributed to the digoxin-induced degradation of REV-ERBα. Taken together, these results show that controlling REV-ERBα proteostasis is an appealing cardioprotective strategy, and bring further support to the rationale, timed use of CTS in prophylactic cardiac preconditioning to MIRI.
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Project description:CD4+ T helper lymphocytes that express interleukin-17 (Th17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in Th17 cell differentiation and function with susceptibility to Crohn’s disease, rheumatoid arthritis, and psoriasis1-3. Thus, the pathway towards differentiation of Th17 cells and, perhaps, of related innate lymphoid cells with similar effector functions4, 5, is an attractive target for therapeutic applications. Mouse and human Th17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORγt, which is required for induction of IL-17 transcription and for the manifestation of Th17-dependent autoimmune disease in mice6. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORγt transcriptional activity. Digoxin inhibited murine Th17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives, 20,22-dihydrodigoxin-21,23-diol (Dig(dhd)) and digoxin-21-salicylidene (Dig(sal)), specifically inhibited induction of IL-17 in human CD4+ T cells. Using these small molecule compounds, we demonstrated that RORγt is imporant for the maintenance of IL-17 expression in mouse and human effector T cells. These data suggest that derivatives of digoxin can be used as chemical probes for development of RORγt-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease. We performed gene expression profiling with total RNA samples isolated from DMSO- or digoxin-treated wildtype or RORγt-deficient cells cultured in Th17 conditions. Total RNA was extracted with TRIzol. RNA was labeled and hybridized to GeneChip Mouse Genome 430 2.0 arrays following the Affymetrix protocols. Data were analyzed in GeneSpring GX11.5.
2011-03-28 | E-GEOD-27241 | biostudies-arrayexpress
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2017-08-19 | E-MTAB-5982 | biostudies-arrayexpress
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Project description:In this study we have evaluated the effect of digoxin in human astrocytes. Our results have shown that non-cytotoxic concentration of digoxin is able to induce astrocytes activation, by affecting cytoskeleton proteins, increasing the expression of pro-inflammatory genes and altering energy metabolism pathways between other mechanisms.
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Project description:Non-medullary thyroid cancer (NMTC) is the most frequent endocrine tumor with in most cases a good prognosis. Unfortunately, 30-40% of patients with metastatic NMTC are unresponsive to 131-I radioactive iodide (RAI) treatment as a result of tumor dedifferentiation. Autophagy has emerged as an important mechanism involved in NMTC dedifferentiation. Furthermore, activation of autophagy by cardiac glycosides such as digoxin has been demonstrated to induce effective in vitro redifferentiation of poorly differentiated and anaplastic thyroid cancer cell lines, thereby restoring sensitivity to RAI treatment. However, the in vivo effects of digoxin treatment on tumor differentiation in NMTC patients remains unclear. In the present retrospective clinical study, archived tumor material obtained from NMTC patients that received digoxin as treatment of heart disease before and after NMTC diagnosis was investigated. By a national PALGA-PHARMO database search, 11 digoxin-treated NMTC patients were included encompassing all major histological NMTC subtypes. In addition, 11 control NMTC patients never treated with digoxin were included that were matched for age, gender, histological tumor type, TNM staging and genetic profile. From the collected tumor material, autophagy activity has been determined by LC3 immunofluorescent staining and RNA expression profiles have been generated by RNA sequencing to assess differential expression of thyroid-specific genes. Interestingly, the results indicate that tumor material from digoxin-treated NMTC patients exhibit significantly higher autophagy activity as compared to tumor material of matched control NMTC patients. Moreover, in all 11 tumor tissues obtained from digoxin-treated NTMC patients the differentiation status was profoundly higher as compared to the matched control NMTC patients, of which the effect size was however dependent on histological NMTC subtypes and genetic profile of the tumor. In conclusion, treatment of NMTC with digoxin before and after NMTC diagnosis is associated with a higher tumor differentiation grade as compared to tumor tissue from closely matched NMTC patients not treated with digoxin. These in vivo data confirm our previous in vitro findings and provide accumulating evidence that digoxin could represent a beneficial adjunctive treatment modality to improve RAI sensitivity in patients with RAI-refractory thyroid carcinoma.
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