8 results on '"Abounader, Roger"'
Search Results
2. Unraveling the hypoxic puzzle: LncRNA LUCAT1 drives glioblastoma in cooperation with HIF1α.
- Author
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Zhang Y, Hudson K, and Abounader R
- Subjects
- Humans, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma metabolism, Glioblastoma pathology, RNA, Long Noncoding genetics, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology
- Published
- 2024
- Full Text
- View/download PDF
3. The blood-brain barrier limits the therapeutic efficacy of antibody-drug conjugates in glioblastoma.
- Author
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Abounader R and Schiff D
- Subjects
- Blood-Brain Barrier, Drug Delivery Systems, Humans, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Immunoconjugates therapeutic use
- Published
- 2021
- Full Text
- View/download PDF
4. A new practical and versatile mouse model of proneural glioblastoma.
- Author
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Abounader R
- Subjects
- Animals, Disease Models, Animal, Mice, Brain Neoplasms, Glioblastoma
- Published
- 2018
- Full Text
- View/download PDF
5. Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha.
- Author
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Olmez I, Love S, Xiao A, Manigat L, Randolph P, McKenna BD, Neal BP, Boroda S, Li M, Brenneman B, Abounader R, Floyd D, Lee J, Nakano I, Godlewski J, Bronisz A, Sulman EP, Mayo M, Gioeli D, Weber M, Harris TE, and Purow B
- Subjects
- Animals, Brain Neoplasms pathology, Cell Line, Tumor, Diacylglycerol Kinase genetics, Female, Humans, Mice, Inbred BALB C, NF-kappa B metabolism, Signal Transduction drug effects, Brain Neoplasms drug therapy, Diacylglycerol Kinase antagonists & inhibitors, Glioblastoma pathology, Ritanserin pharmacology
- Abstract
Background: The mesenchymal phenotype in glioblastoma (GBM) and other cancers drives aggressiveness and treatment resistance, leading to therapeutic failure and recurrence of disease. Currently, there is no successful treatment option available against the mesenchymal phenotype., Methods: We classified patient-derived GBM stem cell lines into 3 subtypes: proneural, mesenchymal, and other/classical. Each subtype's response to the inhibition of diacylglycerol kinase alpha (DGKα) was compared both in vitro and in vivo. RhoA activation, liposome binding, immunoblot, and kinase assays were utilized to elucidate the novel link between DGKα and geranylgeranyltransferase I (GGTase I)., Results: Here we show that inhibition of DGKα with a small-molecule inhibitor, ritanserin, or RNA interference preferentially targets the mesenchymal subtype of GBM. We show that the mesenchymal phenotype creates the sensitivity to DGKα inhibition; shifting GBM cells from the proneural to the mesenchymal subtype increases ritanserin activity, with similar effects in epithelial-mesenchymal transition models of lung and pancreatic carcinoma. This enhanced sensitivity of mesenchymal cancer cells to ritanserin is through inhibition of GGTase I and downstream mediators previously associated with the mesenchymal cancer phenotype, including RhoA and nuclear factor-kappaB. DGKα inhibition is synergistic with both radiation and imatinib, a drug preferentially affecting proneural GBM., Conclusions: Our findings demonstrate that a DGKα-GGTase I pathway can be targeted to combat the treatment-resistant mesenchymal cancer phenotype. Combining therapies with greater activity against each GBM subtype may represent a viable therapeutic option against GBM., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)
- Published
- 2018
- Full Text
- View/download PDF
6. Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma.
- Author
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Feng C, Zhang Y, Yin J, Li J, Abounader R, and Zuo Z
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation physiology, Down-Regulation physiology, Extracellular Signal-Regulated MAP Kinases metabolism, Glioblastoma pathology, Humans, Regulatory Factor X Transcription Factors, Regulatory Factor X1, Signal Transduction genetics, DNA-Binding Proteins metabolism, Glioblastoma metabolism, Hyaluronan Receptors metabolism, Transcription Factors metabolism
- Abstract
Background: The biological functions of regulatory factor (RF)X1, a transcription factor, are not known. Since the RFX1 gene is often epigenetically silenced and clusters of differentiation (CD)44 proteins that regulate cancer cell biology are increased in human glioblastomas, we designed this study to determine whether RFX1 could regulate CD44 expression in glioblastoma., Methods: Regulatory factor X1 was overexpressed in 4 human glioblastoma cell lines. CD44 expression and cell proliferation, apoptosis, and invasion were assayed under in vitro conditions. In vivo growth of human glioblastoma xenografts was determined in mice. The expression of RFX1 and CD44 in human glioblastoma tissues was quantified., Results: A putative RFX1 binding sequence existed in the first exon of the human CD44 gene. The transcription activity of the DNA fragment containing this putative sequence was decreased in cells overexpressing RFX1. Regulatory factor X1 bound to the CD44 gene in glioblastoma cells. It reduced CD44 expression and activated Akt and extracellular signal-regulated kinase, signaling molecules downstream of CD44 to regulate cell proliferation and survival. Overexpression of RFX1 inhibited the survival, proliferation, and transwell invasion of glioblastoma cells and in vivo growth of human glioblastoma xenografts. CD44 overexpression reversed RFX1 effects on cell proliferation. Finally, CD44 protein levels were inversely correlated with RFX1 protein levels in human glioblastoma tissues., Conclusions: These results suggest that RFX1 directly regulates CD44 expression. This mechanism may contribute to RFX1's effects on proliferation, survival, and invasion of glioblastoma cells. Our results provide initial evidence that RFX1 may be an important target/regulator of the malignancy of glioblastoma., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2014
- Full Text
- View/download PDF
7. A miR-297/hypoxia/DGK-α axis regulating glioblastoma survival.
- Author
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Kefas B, Floyd DH, Comeau L, Frisbee A, Dominguez C, Dipierro CG, Guessous F, Abounader R, and Purow B
- Subjects
- 3' Untranslated Regions genetics, Animals, Apoptosis, Blotting, Western, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Movement, Cell Proliferation, Diacylglycerol Kinase genetics, Flow Cytometry, Glioblastoma metabolism, Glioblastoma pathology, Humans, Male, Mice, Mice, Inbred BALB C, Mice, SCID, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Brain Neoplasms mortality, Diacylglycerol Kinase metabolism, Glioblastoma mortality, Hypoxia genetics, MicroRNAs genetics
- Abstract
Background: Despite advances in the treatment of the most aggressive form of brain tumor, glioblastoma, patient prognosis remains disappointing. This failure in treatment has been attributed to dysregulated oncogenic pathways, as observed in other tumors. We and others have suggested the use of microRNAs (miRs) as therapeutic tools able to target multiple pathways in glioblastoma., Methods: This work features PCR quantification of miRs and transient transfection of many glioblastoma cell lines with miRs, followed by cell number analysis, trypan blue staining, alamarBlue assay of cell viability, caspase-3/-7 activity assay, immunoblot of cleaved poly(ADP-ribose) polymerase and fluorescence activated cell sorting and imaging of apoptotic nuclei, cell invasion assays, MRIs of glioblastoma xenografts in mice using transiently transfected cells as well as posttumor treatment with lentiviral vector encoding miR-297, and analysis of miR-297 target diacylglycerol kinase (DGK)-α including immunoblot, 3'UTR luciferase activity, and rescue with DGK-α overexpression. Cell counts and DGK-α immunoblot were also analyzed in the context of hypoxia and with overexpression of heterogeneous ribonucleoprotein L (hnRNPL)., Results: We identified miR-297 as a highly cytotoxic microRNA in glioblastoma, with minimal cytotoxicity to normal astrocytes. miR-297 overexpression reduced in vitro invasiveness and in vivo tumor formation. DGK-α is shown to be a miR-297 target with a critical role in miR-297 toxicity. In addition, hypoxia and its mediator hnRNPL upregulated DGK-α and buffered the cytotoxic effects of miR-297., Conclusion: This work shows miR-297 as a novel and physiologic regulator of cancer cell survival, largely through targeting of DGK-α, and also indicates that hypoxia ameliorates miR-297 toxicity to cancer cells.
- Published
- 2013
- Full Text
- View/download PDF
8. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis.
- Author
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Abounader R and Laterra J
- Subjects
- Animals, Brain Neoplasms metabolism, Humans, Neovascularization, Pathologic metabolism, Proto-Oncogene Proteins c-met metabolism, Brain Neoplasms physiopathology, Hepatocyte Growth Factor metabolism, Neovascularization, Pathologic physiopathology, Signal Transduction physiology
- Abstract
The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor tyrosine kinase c-Met have emerged as key determinants of brain tumor growth and angiogenesis. SF/HGF and c-Met are expressed in brain tumors, the expression levels frequently correlating with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of SF/HGF and/or c-Met in brain tumor cells enhances their tumorigenicity, tumor growth, and tumor-associated angiogenesis. Conversely, inhibition of SF/HGF and c-Met in experimental tumor xenografts leads to inhibition of tumor growth and tumor angiogenesis. SF/HGF is expressed and secreted mainly by tumor cells and acts on c-Met receptors that are expressed in tumor cells and vascular endothelial cells. Activation of c-Met leads to induction of proliferation, migration, and invasion and to inhibition of apoptosis in tumor cells as well as in tumor vascular endothelial cells. Activation of tumor endothelial c-Met also induces extracellular matrix degradation, tubule formation, and angiogenesis in vivo. SF/HGF induces brain tumor angiogenesis directly through only partly known mechanisms and indirectly by regulating other angiogenic pathways such as VEGF. Different approaches to inhibiting SF/HGF and c-Met have been recently developed. These include receptor antagonism with SF/HGF fragments such as NK4, SF/HGF, and c-Met expression inhibition with U1snRNA/ribozymes; competitive ligand binding with soluble Met receptors; neutralizing antibodies to SF/HGF; and small molecular tyrosine kinase inhibitors. Use of these inhibitors in experimental tumor models leads to inhibition of tumor growth and angiogenesis. In this review, we summarize current knowledge of how the SF/HGF:c-Met pathway contributes to brain tumor malignancy with a focus on glioma angiogenesis.
- Published
- 2005
- Full Text
- View/download PDF
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