Luteoloside inhibits proliferation, induces apoptosis and differentiation via β-catenin/c-Myc axis in acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA1129862 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29653384_1.fastq.gz | Fastqsanger.gz | |||
| SRR29653384_2.fastq.gz | Fastqsanger.gz | |||
| SRR29653385_1.fastq.gz | Fastqsanger.gz | |||
| SRR29653385_2.fastq.gz | Fastqsanger.gz | |||
| SRR29653386_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Acute myeloid leukemia (AML) is the most common leukemia in adults, that has a poor prognosis due in part to low response to treatment and high recurrence. And drugs commonly used in conventional treatment strategies often cause serious side-effects. Purpose: To investigate the high efficacy and low toxicity of luteoloside on AML and explore its mechanism of action. Methods:The proliferation of AML cells treated with different concentrations of luteoloside was assessed by the CCK-8 assay and colony formation assay, and apoptosis and differentiation were detected by flow cytometry. RNA-Seq analysis and western blotting were performed to explore the mechanism by which luteoloside exerted anti-AML effects. The patient-derived xenografts (PDX) model was established to assess anti-AML effect of luteoloside in vivo, and construction of an orthotopic AML mouse model explored the combination therapy of luteoloside and cytarabine. Results: Herein, we found that luteoloside could dramatically impair the proliferation and clonogenic capacity of AML cells and induce S phase arrest associated with decrease of Cyclin D1 and increase of Cyclin A2. Furthermore, luteoloside induced apoptosis and promoted differentiation of AML cells. Activation of Wnt/β-catenin signaling by GSK3β inhibitor LiCl reversed the inhibitory effect of luteoloside on AML cell proliferation, apoptosis, and differentiation, due to β-catenin entering into nucleus and reducing the expression of c-Myc. Luteoloside significantly reduced the transplantation rate of primary AML cells in PDX model, and the combination of luteoloside and cytarabine showed a synergistic anti-AML effect in orthotopic AML model. Conclusion: Our findings demonstrate that luteoloside inhibits proliferation, induces apoptosis and differentiation of AML cells via suppression of β-catenin/c-Myc axis, suggesting that luteoloside can be developed as a potential anti-AML drug.
2024-07-04 | GSE271106 | GEO
Project description:Deregulated expression of MYC family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered “undruggable”, and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN- dependent manner and downregulates the MYC pathway on a global level as determined by RNA-seq. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy towards a collection of patient- derived primary glioblastoma and acute myeloid leukemia (AML) ex vivo cultures. Importantly, a variety of normal cells become G1 arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregulates MYC/MYCN, inhibits tumor growth and prolongs survival through apoptosis with little side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for treatment of MYC-driven cancer.
2023-03-08 | GSE197062 | GEO
Project description:The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to an imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depleted key TCA cycle metabolites and, in combination with MYC activation, led to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses revealed that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC- driven lymphoma in vivo. In summary, glutamine supports the viability of MYC- overexpressing cells through an energetic rather than a biosynthetic mechanism.
2022-08-11 | PXD034517 | Pride
Project description:Promising activity of BET protein inhibitors (BETis) is compromised by adaptive or innate resistance in AML. Here, modeling of BETi- persister/resistance (BETi-P/R) in human post-MPN secondary AML (sAML) cells demonstrated accessible and active chromatin in specific super-enhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells; confirming the mechanistic role of the β-catenin-TCF7L2- JMJD6-MYC axis in BETi-resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared to sensitive sAML blasts, displayed higher mRNA and protein expressions of TCF7L2, JMJD6 and c-Myc, and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of co-localization of nuclear β-catenin with TBL1 and TCF7L2 by the small molecule inhibitor BC2059 combined with depletion of BRD4 by BET-PROTAC reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or with patient-derived AML blasts innately resistant to BETi. Therefore, multi- targeted disruption of β-catenin-TCF7L2-JMJD6-MYC axis overcomes adaptive and innate BETi-resistance, exhibiting pre-clinical efficacy against human post-MPN sAML cells.
2020-11-06 | GSE145274 | GEO
Project description:Promising activity of BET protein inhibitors (BETis) is compromised by adaptive or innate resistance in AML. Here, modeling of BETi- persister/resistance (BETi-P/R) in human post-MPN secondary AML (sAML) cells demonstrated accessible and active chromatin in specific super-enhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells; confirming the mechanistic role of the β-catenin-TCF7L2- JMJD6-MYC axis in BETi-resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared to sensitive sAML blasts, displayed higher mRNA and protein expressions of TCF7L2, JMJD6 and c-Myc, and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of co-localization of nuclear β-catenin with TBL1 and TCF7L2 by the small molecule inhibitor BC2059 combined with depletion of BRD4 by BET-PROTAC reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or with patient-derived AML blasts innately resistant to BETi. Therefore, multi- targeted disruption of β-catenin-TCF7L2-JMJD6-MYC axis overcomes adaptive and innate BETi-resistance, exhibiting pre-clinical efficacy against human post-MPN sAML cells.
2020-11-06 | GSE145275 | GEO
Project description:Promising activity of BET protein inhibitors (BETis) is compromised by adaptive or innate resistance in AML. Here, modeling of BETi- persister/resistance (BETi-P/R) in human post-MPN secondary AML (sAML) cells demonstrated accessible and active chromatin in specific super-enhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells; confirming the mechanistic role of the β-catenin-TCF7L2- JMJD6-MYC axis in BETi-resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared to sensitive sAML blasts, displayed higher mRNA and protein expressions of TCF7L2, JMJD6 and c-Myc, and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of co-localization of nuclear β-catenin with TBL1 and TCF7L2 by the small molecule inhibitor BC2059 combined with depletion of BRD4 by BET-PROTAC reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or with patient-derived AML blasts innately resistant to BETi. Therefore, multi- targeted disruption of β-catenin-TCF7L2-JMJD6-MYC axis overcomes adaptive and innate BETi-resistance, exhibiting pre-clinical efficacy against human post-MPN sAML cells.
2020-11-06 | GSE145023 | GEO
Project description:Normal development requires tight regulation of cell proliferation and cell death. Here, we investigated these control mechanisms in the hyaloid vessels, a temporary vascular network in the mammalian eye that requires a Wnt/β-catenin response for scheduled regression. Transcriptome analysis of the postnatal day 5 mouse hyaloid showed expression of several Wnt pathway proteins. We investigated whether the hyaloid Wnt response was linked to the oncogene Myc, and the cyclin-dependent kinase inhibitor P21 (CDKN1A), both established regulators of cell cycle progression and cell death. Our analysis showed that the Wnt pathway coreceptors LRP5 and LRP6 have overlapping activities mediating the Wnt/β-catenin signaling in hyaloid vascular endothelial cells (VECs). We also showed that both Myc and Cdkn1a are downstream of the Wnt response and are required for hyaloid regression but for different reasons. Conditional deletion of Myc in VECs suppressed both proliferation and cell death. By contrast, conditional deletion of Cdkn1a resulted in VEC over-proliferation that countered the effects of cell death on regression. When combined with analysis of MYC, and P21 protein levels, this analysis suggests that a Wnt/β-catenin, MYC-P21 pathway regulates scheduled hyaloid vessel regression.
2018-06-15 | GSE113294 | GEO
Project description:One of the transcriptional targets of b-catenin/TCF and a key downstream effector of the WNT/b-catenin pathway in several tissues is the MYC proto-oncogene, which encodes for a transcription factor that is a master regulator of proliferation- and growth-related genes. However, several evidences indicate that this epistatic relationship does not seem to occur in liver: indeed Myc was not induced upon b-catenin activation driven by APC loss, and Myc deletion in hepatocytes does not suppress the effects of APC loss on cell proliferation and liver zonation. Besides, there are indications that the two pathways can be independently activated, and cooperate during tumorigenesis. In particular, MYC amplification and b-catenin mutations showed a tendency toward co-occurrence in either adult HCC or aggressive childhood hepatoblastoma, and MYC-driven HCC in experimental mouse models frequently acquired activating mutations in b-catenin. In order to address whether these observations reflect a functional cross-talk between the two pathways that may occur in a specific molecular subgroup of HCC patients, we generated a new mouse model allowing conditional activation of MYC and -catenin in hepatocytes. This model demonstrated a strong cooperativity between the two oncogenes in promoting liver tumorigenesis. Our data indicate that this cooperation occurs mainly through unrestrained proliferation of liver cells that requires the activity of the transcriptional co-factors Yap and Taz.
2020-05-12 | GSE138296 | GEO
Project description:HCP5 inhibits apoptosis via c-Myc transcriptional regulation mediated by UTP3 based chromatin-RNA-binding protein interaction
| PRJNA824352 | ENA
Project description:This study demonstrates that HCP5/UTP3/c-Myc/VAMP3 axis plays important role in inhibition of cancer cell apoptosis and HCP5 can be targeted to contribute to cell apoptosis induced by cytotoxic agents.
2022-10-26 | GSE200270 | GEO