| Urokinase plasminogen activator receptor and/or matrix metalloproteinase-9 inhibition induces apoptosis signaling through lipid rafts in glioblastoma xenograft cells. | |
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MedLine Citation:
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PMID: 20716639 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Small interfering RNA (siRNA)-mediated transcriptional knockdown of urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9), alone or in combination, inhibits uPAR and/or MMP-9 expression and induces apoptosis in the human glioblastoma xenograft cell lines 4910 and 5310. siRNA against uPAR (pU-Si), MMP-9 (pM-Si), or both (pUM-Si) induced apoptosis and was associated with the cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase. Furthermore, protein levels of the Fas receptor (APO-1/CD-95) were increased following transcriptional inactivation of uPAR and/or MMP-9. In addition, Fas siRNA against the Fas death receptor blocked apoptosis induced by pU-Si, pM-Si, or pUM-Si, thereby indicating the role for Fas signaling in pU-Si-, pM-Si-, or pUM-Si-mediated apoptotic cell death of human glioma xenograft cells. Thus, transcriptional inactivation of uPAR and/or MMP-9 enhanced localization of Fas death receptor, Fas-associated death domain-containing protein, and procaspase-8 into lipid rafts. Additionally, disruption of lipid rafts with methyl β cyclodextrin prevented Fas clustering and pU-Si-, pM-Si-, or pUM-Si-induced apoptosis, which is indicative of coclustering of Fas death receptor into lipid rafts in the glioblastoma xenograft cell lines 4910 and 5310. These data indicate the crucial role of the clusters of apoptotic signaling molecule-enriched rafts in programmed cell death, acting as concentrators of death receptors and downstream signaling molecules, and as the linchpin from which a potent death signal is launched in uPAR- and/or MMP-9-downregulated cells. |
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Authors:
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Chandramu Chetty; Sajani S Lakka; Praveen Bhoopathi; Christopher S Gondi; Krishna Kumar Veeravalli; Daniel Fassett; Jeffrey D Klopfenstein; Dzung H Dinh; Meena Gujrati; Jasti S Rao |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-17 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 9 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-10 Completed Date: 2011-02-17 Revised Date: 2012-12-10 |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 2605-17 Citation Subset: IM |
Affiliation:
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Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61605, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, CD95 / metabolism Apoptosis / genetics Brain Neoplasms / enzymology, genetics, pathology, therapy* Caspase 8 / metabolism Cell Line, Tumor Down-Regulation Glioblastoma / genetics, metabolism, pathology, therapy* Humans Matrix Metalloproteinase 9 / genetics, metabolism Matrix Metalloproteinase Inhibitors* Membrane Microdomains / genetics, metabolism* Mice Mice, Nude RNA, Small Interfering / administration & dosage*, genetics Receptors, Urokinase Plasminogen Activator / antagonists & inhibitors*, genetics, metabolism Signal Transduction Transcriptional Activation Transfection Transplantation, Heterologous Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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NS 047699/NS/NINDS NIH HHS; R01 CA116708/CA/NCI NIH HHS; R01 NS047699-07/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD95; 0/Matrix Metalloproteinase Inhibitors; 0/RNA, Small Interfering; 0/Receptors, Urokinase Plasminogen Activator; EC 3.4.22.-/Caspase 8; EC 3.4.24.35/Matrix Metalloproteinase 9 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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