Thyrointegrin αvβ3 antagonist with potent Affinity in the treatment of Glioblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE183773 | GEO | 2021/09/11
REPOSITORIES: GEO
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Project description:Microarray analysis was carried out on Glioblastoma (GBM 10181360, GBM 021913 and U87 cells), Bladder cancer (JBV253), skin cancer (A375) and Acute Myelod Leukemia (AML) (KG1A and K562 cells) exposed to fb-PMT at 30 µM concentration. Our genome-wide microarray screens demonstrated that fb-PMT appears to exert its potent anticancer actions on human cancer cells through the molecular interference mechanism with multiple signaling pathways supporting growth and survival of leukemic cells. Notably, fb-PMT had a significant effect on different molecular pathways that contribute to the anticancer activity such as cell cycle control (MYC), survival and maintenance of stem cells (HIF1A; TFAP2C), essential features of the malignant phenotype (TWIST1; SNAI). Furthermore, the fb-PMT-induced significant transcriptional pathway’s activation includes RB1; IRF9; MAML1; RAP1A; and GATA4 pathways, which known to play an important role in anticancer activity. Finally, Consistent with our previous reports on the crosstalk between integrin αvβ3 and ERα which contributes to the induced proliferation of cancer cells, we found that fb-PMT interference with estrogen signaling. The αvβ3 agonist (thyroid hormone) was associated with increased phosphorylation and nuclear enrichment of estrogen receptor α (ERα).
2021-09-11 | GSE183772 | GEO
Project description:Thyrointegrin αvβ3 antagonist with potent Affinity in the treatment of Glioblastoma
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Project description:How cancer cells adapt to hypoxia during tumor development remains an important question. The hypothesis tested in the present study was that tumor cell-derived exosome vesicles (also known as microvesicles or extracellular vesicles) are mediators of hypoxia-dependent intercellular signaling in glioblastoma (GBM), i.e. highly aggressive brain tumors characterized by hypoxia and a vascular density that is among the highest of all human malignancies. In vitro hypoxia experiments and studies with patient materials reveal the enrichment in exosomes of hypoxia-regulated mRNAs and proteins, several of which were associated with poor patient prognosis. We show that cancer cell exosomes mediate hypoxia-dependent, phenotypic modulation of stromal cells in vitro and ex vivo, resulting in accelerated GBM tumor angiogenesis and growth in mice. These data suggest that exosomes constitute potent mediators of hypoxia-driven tumor development, and circulating multiparameter biomarkers of tumor hypoxia. U87 MG glioblastoma cells were grown at normoxic (21% oxygen) or hypoxic (1% oxygen) conditions for 48 hours. Conditioned media from normoxic and hypoxic cells were then used to isolate exosomes by differential centrifugation. Both cells and exosomes were lysed in Trizol reagent, and RNA was isolated.Total RNA from all samples (four types of samples in three biological repilicates) was subjected to genome-wide transcriptional analysis with Illumina HumanHT-12 V3.0 expression beadchip. Gene expression profile obtained from hypoxic U87 MG glioblastoma cells was compared to the profile of normoxic control cells. Analogically, gene expression profile obtained from hypoxic U87 MG cells was compared to the profile of exosomes secreted by normoxic U87 MG cells.
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Project description:TMZ resistance is one of the main reasons why treatment of glioblastoma (GBM) fails. In order to investigate the underlying mechanism associated with TMZ resistance, we conducted a cytoplasmic proteome research of U87 cells treated with TMZ for 1 week. A total of 162 DEPs including 66 up-regulated proteins and 96 down-regulated proteins were identified.
2018-10-23 | PXD007759 | Pride
Project description:The purpose of this study is to determine whether the combination of two agents, INC280 and bevacizumab, is safe and effective when administered to patients with Glioblastoma Multiforme (GBM) who have progressed after receiving prior therapy or who have unresectable GBM.
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Project description:Brusatol (Bru), a Chinese herbal extract, has a variety of anti-tumor effects. However, little is known regarding its role and underlying mechanism in glioblastoma cells. Here, we found that Bru could inhibit the proliferation of glioblastoma cells in vivo and in vitro. Besides, it also had an inhibitory effect on human primary glioblastoma cells. In order to further study the underlying mechanism of Bru’s action on GBM, we performed RNA sequencing array on GBM cells treated by Bru with IC50 for 48 hours. A log2 fold change >1.0 and a P < 0.05 were used as cutoff criteria. The volcano plots results showed that Bru significantly changed the mRNA expression pattern in U251 (819 upregulated genes and 954 downregulated genes) and U87 (485 upregulated genes and 266 downregulated genes) cells. Then, we subjected these differentially expressed genes to the Reactome pathway database (https://reactome.org), which provides molecular details of signal transduction, transport, DNA replication, metabolism, and other cellular processes as an ordered network of molecular transformations in a single, consistent data model. Reactome enrichment analysis indicated that the collagen and extracellular matrix related pathways (Italic Script with *) were mainly involved in Bru-treated GBM cells. Subsequently, we used the Venn diagram analysis (VDA) to display the shared genes between U251 and U87 cells and finally determined that ESM1, an important factor in extracellular matrix formation, changed obviously by Bru treatment. Down-regulating the expression of ECM1 via transfecting siRNA could weaken the proliferation and invasion of glioblastoma cells and promote the inhibitory effect of Bru treatment. Lentivirus-mediated overexpression of ECM1 could effectively reverse this weakening effect. Our findings indicated that Bru could inhibit the proliferation and invasion of glioblastoma cells by suppressing the expression of ECM1, and Bru might be a novel effective anticancer drug for glioblastoma cells.
2021-12-31 | GSE184859 | GEO
Project description:Purpose:Glioblastoma (GBM) is the most common primary brain tumor in adults with poor prognosis and short medial survival after therapy. we have utilized U87-MG cell line as a human GBM cell model and human brain HEB cell line as non-neoplastic brain cell cultured in normoxia and 1% O2 hypoxia for transcriptional profiling to gain further insight into the molecular underpinnings that maintained the properties of GBM andclarify the molecular mechanism of hypoxia resistance of GBM. Methods:We have utilized U87-MG cell line as a human GBM cell model and human brain HEB cell line as non-neoplastic brain cell cultured in normoxia and 1% O2 hypoxia for transcriptional profiling. And validating the analysis results with specimens of GBM patients. Results: Firstly, the resulting data set revealed previously unknown proteins, including AKR1B1, MT2A, UBC, EEF1A1 and MTRNR2l2 in U87-MG cells, which promoted GBM characters through MAPK pathway. Meanwhile, we found that toll-like pathway was a new avenue mediating the function of inflammatory response in GBM. Furthermore, The results suggested that cytokine TGF-β1 and HIFs’ targeted genes, including HMOX1 and STC1 could be regard as hypoxic markers for GBM. Conclusion:Taken together, our study identified new potential biomarkers and illustrated the genes associated with inflammation in GBM. More importantly, the unique pattern to hypoxia implied new insight for the GBM research of hypoxia resistance and recurrence in future.
2019-09-11 | GSE77307 | GEO
Project description:Glioblastoma (GBM), classified as a grade 4 glioma, is the most prevalent intrinsic malignancy of the central nervous system. Glioblastoma stem cells (GSCs) are small populations of GBM cells with self-renewal and multilineage differentiation capabilities and are considered responsible for the tumorigenesis and development of GBM. POSTN secreted from glioblastoma stem cells can recruit microglia and upregulate CD70 expression in microglia through the αVβ3/PI3K/AKT/NFκB pathway, which in turn promotes Treg development and functionality and supports the formation of an immunosuppressive tumor microenvironment.
2024-08-01 | GSE273251 | GEO
Project description:Four human mesenchymal stem cells (hMSC) clones (MSC-1, MSC-2, MSC-3, MSC-4) and three different glioblastoma multiformae (GBM) cell lines (U87-MG, U251, U373) were used to study their mutual paracrine interactions in the indirect co-cultures compared to their monocultures, which were grown under the same experimental conditions. The effects on cell growth, proliferation and invasion in matrigel were quantified. Further on, bioinformatic tools were used to relate these results to the data obtained from cytokine macroarrays and DNA microarrays that revealed proteins and genes significantly involved in the interaction. We showed that hMSC are responsible for the impairment of GBM cell invasion and growth, possibly via induction of their senescence. On the other hand, U87-MG cells even more strongly inversely affected some of these characteristics in hMSCs. We found several chemokines that may account for changed co-cultured cells’ phenotype, affecting genes associated with proliferation and senescence. CCL2/MCP-1 was collectively identified as the most significantly regulated chemokine during hMSC and U87-MG paracrine signalling. Its role in U87-MG cell invasion was also functionally confirmed. Microarray data deposited here contain gene expression data from three biological replicates of monocultures and indirect co-cultures of MSC-4 and U87-MG cells, representing 12 microarrays. Three biological replicates of four cell set-ups were performed: MSC-4 monoculture, U87-MG monoculture, MSC-4 co-cultured with U87-MG (in Boyden chambers) and U87-MG co-cultured with MSC-4 (in Boyden chambers).
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Project description:Glioblastoma (GBM) patient-derived orthotopic xenografts (PDOXs) were derived from organotypic spheroids obtained from patient tumor samples. To detect whether gene expression profiles of GBM patient tumors are retained in PDOXs, we performed genome-wide transcript analysis by human-specific microarrays . In parallel, we analyzed GBM cell cultures and corresponding intracranial xenografts from stem-like (NCH421k, NCH644) and adherent GBM cell lines (U87, U251). PDOXs show a better transcriptomic resemblance with patient tumors than other preclinical models. The major difference is largely explained by the depletion of human-derived non-malignant cells.
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