The STAT3-MYC Axis Promotes Survival of Leukemia Stem Cells by Regulating SLC1A5 and Oxidative Phosphorylation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE183036 | GEO | 2021/09/01
REPOSITORIES: GEO
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Project description:The STAT3-MYC Axis Promotes Survival of Leukemia Stem Cells by Regulating SLC1A5 and Oxidative Phosphorylation
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Project description:Endothelin receptor A (EDNRA) has been reported to play various crucial physiological roles and has been shown to be associated with the pathology of several diseases, including colorectal cancer (CRC). However, the molecular mechanisms of EDNRA in the development of human CRC have not been fully elucidated to date. In this context, the present study was performed to investigate biological functions and novel downstream signaling pathways affected by EDNRA, during CRC progression. First, using public data repositories, it was observed that the EDRNA expression levels were markedly increased in CRC tissues, as compared to normal tissues. Patients with CRC with an increased EDNRA expression exhibited a significantly decreased survival rate in comparison with those with a lower EDNRA expression. Furthermore, a positive correlation between the levels of EDNRA and its ligand, EDN1, was found in CRC tissues. The ectopic expression of EDNRA or its ligand, EDN1, promoted, whereas the silencing of EDNRA or EDN1 decreased cell proliferation and migration in vitro. To elucidate the signaling pathways involved in the regulation of EDNRA expression in CRC cells, a phosphokinase array analysis was performed, and it was observed that the knockdown of EDNRA substantially suppressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in CRC cells. Of note, STAT3 silencing simultaneously decreased EDN1 and EDNRA expression, with the expression of EDN1 and/or EDNRA appearing to be directly regulated by binding STAT3 to their promoter region, according to chromatin immunoprecipitation and promoter assays, ultimately indicating a positive feedback loop in the expression of EDNRA and EDN1. It was also observed that treatment with an EDNRA antagonist (macitentan), alone or in combination with cisplatin, suppressed cell growth and migration ability, and induced cell apoptosis. Collectively, these data suggest a critical role of the EDN1/EDNRA signaling pathway in CRC progression. Thus, the pharmacological intervention of this signaling pathway may prove to be a potential therapeutic approach for patients with CRC.
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Project description:The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the culprit molecular underpinnings, we designed an approach that combines sensitivity to drugs with an integrated systems-biology characterization. Sensitivity to inhibitors of the ERBB family of receptor tyrosine kinases correlated with their overexpression, suggesting a causative link. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to oncogenic signaling hubs including evolutionary conserved STAT3. Indeed, inhibition of ERBB blocked phosphorylation of STAT3 and arrested cancer cells. Blockade of ERBB signaling prevented tumor growth in a xenograft model and resulted in recovery of MHC-I gene expression. This link between the hyperactive ERBB-STAT3 axis and decreased MHC-I mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and lets us propose a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD.
2019-01-18 | PXD009283 | Pride
Project description:TCRαβ CD8 large granular lymphocyte (LGL) leukemia is a rare heterogeneous hematological disorder with a chronic disease course that mostly affects elderly. It is generally accepted that LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of dysregulation of mainly the STAT3 but also to some extent the ERK pathway, which are constitutively activated. In approximately 40% of patients this is due to STAT3 activating mutations, but for the other 60% it remains to be elucidated, why the STAT3 pathway is chronically activated. miRNAs are one of the most potent regulators in health and disease and are also linked with various leukemias. Therefore, we hypothesized that aberrant miRNA expression could contribute to dysregulation of the STAT3 pathway. miRNA sequencing in LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miRNA181a. Furthermore, gene set enrichment analysis (GSEA) of miRNA181a implicated its involvement in the STAT3 and ERK1/2 pathways. Phosphoflow analysis of STAT3, ERK1/2 in miR181a-transfected human CD8 T cells revealed that miR181a overexpression results in STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line model, we have now established that miR181a is the common actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition in LGL leukemia patients. Additionally, miR181a induces ERK1/2 phosphorylation by inhibition of DUSP6. Taken together, our data show that miR181a is the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
2021-12-01 | GSE159878 | GEO
Project description:TCRαβ CD8 large granular lymphocyte (LGL) leukemia is a rare heterogeneous hematological disorder with a chronic disease course that mostly affects elderly. It is generally accepted that LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of dysregulation of mainly the STAT3 but also to some extent the ERK pathway, which are constitutively activated. In approximately 40% of patients this is due to STAT3 activating mutations, but for the other 60% it remains to be elucidated, why the STAT3 pathway is chronically activated. miRNAs are one of the most potent regulators in health and disease and are also linked with various leukemias. Therefore, we hypothesized that aberrant miRNA expression could contribute to dysregulation of the STAT3 pathway. miRNA sequencing in LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miRNA181a. Furthermore, gene set enrichment analysis (GSEA) of miRNA181a implicated its involvement in the STAT3 and ERK1/2 pathways. Phosphoflow analysis of STAT3, ERK1/2 in miR181a-transfected human CD8 T cells revealed that miR181a overexpression results in STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line model, we have now established that miR181a is the common actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition in LGL leukemia patients. Additionally, miR181a induces ERK1/2 phosphorylation by inhibition of DUSP6. Taken together, our data show that miR181a is the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
2021-12-01 | GSE159819 | GEO
Project description:STAT3 (Signal transducer and activator of transcription 3) expression is associated with with t(12;21) acute lymphoblastic leukaemia (ALL) and it is crucial for the survival of the t(12;21) ALL . Our study investigated the STAT3 regulated pathways and discovered a novel STAT3-TP53 axis in B-ALL. In order to determine the STAT3 regulated pathways in t(12;21) ALL cells, we performed RNAseq analysis on the Pre-B Acute Lymphoblastic Leukemia (ALL) cell line REH, treated with DMSO vehicle control in comparison to 50uM S3I-021, a specific STAT3 inhibitor
2024-01-31 | GSE179333 | GEO
Project description:Ubiquitin-like, containing PHD and RING finger domain, (UHRF) family members are overexpressed putative oncogenes in several cancer types. We evaluated the protein abundance of UHRF family members in acute leukemia. A marked overexpression of UHRF1 protein was observed in ALL compared with AML. An analysis of human leukemia transcriptomic datasets revealed concordant overexpression of UHRF1 in B-Cell and T-Cell ALL compared with CLL, AML, and CML. In-vitro studies demonstrated reduced cell viability with siRNA-mediated knockdown of UHRF1 in both B-ALL and T-ALL, associated with reduced c-Myc protein expression. Mechanistic studies indicated that UHRF1 directly interacts with c-Myc, enabling ALL expansion via the CDK4/6-phosphoRb axis. Our findings highlight a previously unknown role of UHRF1 in regulating c-Myc protein expression and implicate UHRF1 as a potential therapeutic target in ALL.
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Project description:Many patients have cancers that have increased activity of a protein called STAT3 that contributes critically to the development and growth of their cancer. Despite our knowledge of STAT3’s importance to cancer, scientists and doctors have not developed a drug that targets it and that patients can take to treat their cancer more effectively than treatments that are now available. Tvardi Therapeutics, Incorporated has developed a compound, TTI-101, which can be given by mouth and acts as a direct inhibitor of STAT3. Administration of TTI-101 to mice demonstrated that it blocked growth of cancers of the breast, head and neck, lung, and liver and it was safe when administered at high doses to mice, rats, and dogs. In this application, Tvardi is proposing to further develop TTI-101 for treatment of solid tumors for which the prognosis is dismal. The investigators will determine how safe it is when administered to patients with cancer, determine whether an adequate dose can be administered to patients with cancer that will block STAT3 in their cancer, and determine whether treatment with TTI-101 leads to reduced growth of their cancer.
| 2247646 | ecrin-mdr-crc
Project description:Stat3-Bdnf-TrkB axis promotes alveolar regeneration
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Project description:Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism.
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