Identification of Homoharringtonine as a potent inhibitor of glioblastoma cell proliferation and migration.
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ABSTRACT:
PROVIDER: PRJNA745902 | ENA |
REPOSITORIES: ENA
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Project description:We previously demonstrated that Annexin A2 (ANXA2) is a pivotal mediator of the pro-oncogenic features displayed by glioblastoma (GBM) tumors, the deadliest adult brain malignancies. In GBM, ANXA2 sustains a transcriptional program involved in cell stemness, proliferation and invasion, negatively impacting patient prognosis. Transcriptional signatures obtained by the modulation of ANXA2 activity/levels were functionally mapped through the QUADrATiC bioinformatic tool for compound identification. Selected compounds were screened by cell proliferation and migration assays in primary GBM cells. Screening of compounds selected through QUADrATiC identified HHT as a potent inhibitor of GBM cell motility and proliferation. A further molecular characterization of the effects displayed by HHT, confirmed its ability to inhibit a transcriptional program involved in cell migration and invasion. Moreover, we demonstrated that the multiple antitumoral effects displayed by HHT are correlated to the inhibition of a PDGFRα-dependent intracellular signaling through the impairment of STAT3 and RhoA axes. Homoharringtonine is a potent inhibitor of GBM cell proliferation and migration
2022-07-29 | GSE179924 | GEO
Project description:The invasion capacity is one of the hallmarks of glioblastoma (GBM) cells. We found that ODZ1 which is mainly expressed in fetal brain, plays a crucial role in the migration and proliferation of GBM stem-like cells (GSCs). Introduction of the entire ODZ1 or its intracellular fragment in ODZ1-deficient cells promotes migration and invasion in 2D and 3D substrates and in chicken embryo and mouse xenograft models. Moreover, ODZ1 increases the proliferation of GSCs in culture and generates bigger tumor masses in the brain of xenografted mice. Consistently, higher levels of ODZ1 are correlated with lower survival both in patients and in xenograft models. On note, ODZ1 promotes the transcriptional activation of RhoA and ODZ1-induced proliferation and invasion activities were blocked by inhibiting RhoA-ROCK axis. Overall, we describe a novel cancer-associated gene involved in the progression of glioblastoma, providing a putative prognostic marker and a new target for therapeutic strategies.
2018-02-01 | GSE65526 | GEO
Project description:Glioblastoma is the most frequent and aggressive primary astrocytoma in adults. The high migration ability of the tumor cells is an important reason for the high recurrence rate and poor prognosis of glioblastoma. Recently, emerging evidence has shown that the migration ability of glioblastoma cell was inhibited upon the activation of aryl hydrocarbon receptor (AhR), suggesting potential anti-tumor effects of AhR agonists. Rutaecarpine is a natural compound with potential tumor therapeutic effects which can possibly bind to AhR. However, its effect on the migration of glioblastoma is unclear. Therefore, we aim to explore the effects of rutaecarpine on the migration of human glioblastoma cells U87 and the involvements of the AhR signaling pathway. The results showed that: (i) compared with other structural related alkaloids, like evodiamine and dehydroevodiamine, rutaecarpine was a more potent AhR activator, and has stronger inhibitory effect on the glioblastoma cell migration; (ii) rutaecarpine decreased the migration ability of U87 cells in an AhR-dependent manner; (iii) AhR mediated the expression of a tumor suppressor interleukin 24 (IL24) induced by rutaecarpine, and AhR-IL24 axis was involved in the anti-migratoryeffects of rutaecarpine on the glioblastoma. Besides IL24, other motility related genes were proposed to participate in the migration regulation process of rutaecarpine by RNA-Seq analysis. These data suggest that rutaecarpine is a natural AhR agonist that could inhibit the migration of glioblastomaandbe a potential candidate for developing therapeutic drug against glioblatoma.
2021-12-07 | GSE183606 | GEO
Project description:Glioblastoma cells are characterized by a highly invasive behavior whose mechanisms are not yet understood. Using the wound healing and Boyden chamber assays we compared in the present study the migration and invasion abilities of 5 glioblastoma cell lines (DK-MG, GaMG, U87-MG, U373-MG, SNB19) differing in p53 and PTEN status. We also analyzed by Western blotting the expression of PTEN, p53, mTOR and several other marker proteins involved in cell adhesion, migration and invasion. Among 5 cell lines, GaMG cells exhibited the fastest rate of wound closure, whereas U87-MG cells showed the most rapid chemotactic migration in the Boyden chamber assay. In DK-MG and GaMG cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG, U373-MG and SNB19 cells preferentially expressed F-actin in filopodia and lamellipodia. Moreover, the two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) were found to exhibit the fastest invasion rates through the Matrigel matrix. Here, we performed a gene expression profiling of the five glioblastoma cell lines to examine the molecular framework of differences in invasive behavior to find possible targets for chemo- and radiation therapy.
2014-09-05 | E-GEOD-53124 | biostudies-arrayexpress
Project description:It is currently challenging to adequately model the growth and migration of glioblastoma using 2D in vitro culture systems as they quickly lose the original, patient-specific identity and heterogeneity. However, with the advent of 3D cell cultures and human induced pluripotent stem cells (iPSCs)-derived cerebral organoids (COs), studies demonstrate that the glioblastoma-cerebral organoid (GLICO) co-culture model helps to preserve the phenotype of the patient-specific tissue. Here we aimed to set up such a model using mature COs and develop a pipeline for subsequent analysis of co-cultured glioblastoma. Our data demonstrates that the growth and migration of the glioblastoma cell line within the mature COs are significantly increased in the presence of extracellular matrix proteins, shortening the time needed for glioblastoma to initiate migration. We also describe in detail the method for the visualization and quantification of these migrating cells within the GLICO model. Lastly, we show that this co-culture model (and the human brain-like microenvironment) can significantly transform the gene expression profile of the established U87 glioblastoma cell line into proneural and classical glioblastoma cell types.
2023-02-22 | GSE216626 | GEO
Project description:<h4><strong>BACKGROUND:</strong> Elevated choline kinase alpha (ChoK) is observed in most solid tumours including glioblastomas (GBM), yet until recently, inhibitors of ChoK have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with GBM therapy resistance, we hypothesised that tumour hypoxia could be responsible for such limitations. We therefore evaluated in GBM cells, the effect of hypoxia on the function of JAS239, a potent ChoK inhibitor.</h4><h4><strong>METHODS:</strong> Rodent (F98 and 9L) and human (U-87 MG and U-251 MG) GBM cell lines were subjected to 72 hours of hypoxia conditioning and treated with JAS239 for 24 hours. NMR metabolomic measurements and analyses were performed to evaluate the signalling pathways involved. In addition, cell proliferation, cell cycle progression and cell invasion were measured in cell monolayers and 3D spheroids, with or without JAS239 treatment in normoxic or hypoxic cells to assess how hypoxia affects JAS239 function.</h4><h4><strong>RESULTS:</strong> Hypoxia and JAS239 treatment led to significant changes in the cellular metabolic pathways, specifically the phospholipid and glycolytic pathways associated with a reduction in cell proliferation via induced cell cycle arrest. Interestingly, JAS239 also impaired GBM invasion. However, JAS239 effects were variable depending on the cell line, reflecting the inherent heterogeneity observed in GBMs.</h4><h4><strong>CONCLUSION:</strong> Our findings indicate that JAS239 and hypoxia can deregulate cellular metabolism, inhibit proliferation and alter cell invasion. These results may be useful for the design of new therapeutic strategies based on ChoK inhibition that can act on multiple pro-tumorigenic features.</h4>
2024-06-18 | MTBLS6212 | MetaboLights
Project description:Glioblastoma cells are characterized by a highly invasive behavior whose mechanisms are not yet understood. Using the wound healing and Boyden chamber assays we compared in the present study the migration and invasion abilities of 5 glioblastoma cell lines (DK-MG, GaMG, U87-MG, U373-MG, SNB19) differing in p53 and PTEN status. We also analyzed by Western blotting the expression of PTEN, p53, mTOR and several other marker proteins involved in cell adhesion, migration and invasion. Among 5 cell lines, GaMG cells exhibited the fastest rate of wound closure, whereas U87-MG cells showed the most rapid chemotactic migration in the Boyden chamber assay. In DK-MG and GaMG cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG, U373-MG and SNB19 cells preferentially expressed F-actin in filopodia and lamellipodia. Moreover, the two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) were found to exhibit the fastest invasion rates through the Matrigel matrix.
2014-09-05 | GSE53124 | GEO
Project description:Bromodomain and extraterminal domain (BET) proteins have emerged as therapeutic targets in multiple cancers, including the most common primary adult brain tumor glioblastoma (GBM). Although several bet inhibitors have entered clinical trials, few are brain penetrant. We have generated UM-002, a novel brain penetrant BET inhibitor that reduces GBM cell proliferation in vitro and in a human cerebral brain organoid model. Since UM-002 is more potent than other BET inhibitors, it could potentially be developed for GBM treatment. Furthermore, UM-002 treatment reduces the expression of cell-cycle related genes in vivo, and reduces the expression of invasion related genes within the non-proliferative cells present in tumors as measured by single cell RNAsequencing. These studies suggest that BET inhibition alters the transcriptional landscape of GBM tumors, which has implications for designing combination therapies. Importantly, they also provide an integrated dataset that combines in vitro and ex vivo studies with in vivo single-cell RNA-sequencing to characterize a novel BET inhibitor in GBM.
2021-12-01 | GSE173146 | GEO
Project description:Glioblastoma, the most aggressive primary brain cancer, has dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we here systematically screen repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling >2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug-target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of >1 million compounds with high patient validation accuracy. Deep multi-modal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the antidepressant Vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.
| MSV000090357 | MassIVE
Project description:Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumor. Although alkylating agents (such as temozolomide (TMZ)) are widely used as first-line treatments for GBM, they often cause chemoresistance and are poorly effective for recurrent GBM. Therefore, anti-GBM drugs with novel mechanism are urgently needed clinically. Here, we report an effective Ca2 +-calcineurin-NFAT signaling pathway inhibitor (Pimavanserin), which exhibits effective anti-tumor activity against GBM. Pimavanserin induces GBM cell cycle arrest in G1/S, promotes cell apoptosis and inhibits tumor cell proliferation and metastasis. Through an in-depth study of the mechanism, it is found that Pimavanserin eliminates NFAT nuclear translocation by inhibiting the formation of puncta of STIM1. Subsequent transcriptomic and proteomic analysis unveiled that PIM can down-regulate E2F, MYC ATR and AuroraA/B signaling pathways to inhibit GBM cancer growth both in vitro and in vivo. In addition, the upregulated genes were mainly associated with cholesterol homeostasis and fatty acid synthesis, which may underlie the mechanism of PIM’s phospholipidosis side effect. This article is the first report of Pimavanserin as an anti- GBM drug.
2020-12-17 | PXD023207 |