| uPAR and cathepsin B inhibition enhanced radiation-induced apoptosis in gliomainitiating cells. | |
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MedLine Citation:
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PMID: 22573309 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glioblastomas present as diffuse tumors with invasion into normal brain tissue and frequently recur or progress after radiation as focal masses because of glioma-initiating cells. The role of the urokinase-type plasminogen activator receptor (uPAR) and cathepsin B in stem-like phenotype has been extensively studied in several solid tumors. In the present study, we demonstrated that selection of glioma-initiating cells using CD133 expression leads to a specific enrichment of CD133(+) cells in both U87 and 4910 cells. In addition, CD133(+) cells exhibited a considerable amount of other stem cell markers, such as Nestin and Sox-2. Radiation treatment significantly enhanced uPAR and cathepsin B levels in glioma-initiating cells. To downregulate radiation-induced uPAR and cathepsin B expression, we used a bicistronic shRNA construct that simultaneously targets both uPAR and cathepsin B (pCU). Downregulation of uPAR and cathepsin B using pCU decreased radiation-enhanced uPAR and cathepsin B levels and caused DNA damage-induced apoptosis in glioma cell lines and glioma-initiating cells. The most striking finding of this study is that knockdown of uPAR and cathepsin B inhibited ongoing transcription by suppressing BrUTP incorporation at γH2AX foci. In addition, uPAR and cathepsin B gene silencing inversely regulated survivin and H2AX expression in both glioma cells and glioma-initiating cells. Pretreatment with pCU reduced radiation-enhanced expression of uPAR, cathepsin B, and survivin and enhanced DNA damage in pre-established glioma in nude mice. Taken together, our in vitro and in vivo findings suggest that uPAR and cathepsin B inhibition might serve as an adjunct to radiation therapy to target glioma-initiating cells and, therefore, for the treatment of glioma. |
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Authors:
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Rama Rao Malla; Sreelatha Gopinath; Kiranmai Alapati; Bharathi Gorantla; Christopher S Gondi; Jasti S Rao |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-05-09 |
Journal Detail:
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Title: Neuro-oncology Volume: 14 ISSN: 1523-5866 ISO Abbreviation: Neuro-oncology Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-06-06 Completed Date: 2012-10-11 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 100887420 Medline TA: Neuro Oncol Country: England |
Other Details:
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Languages: eng Pagination: 745-60 Citation Subset: IM |
Affiliation:
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Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / radiation effects* Blotting, Western Cathepsin B / antagonists & inhibitors*, genetics, metabolism Cell Cycle / radiation effects Cell Line, Tumor Down-Regulation Fluorescent Antibody Technique Glioma / metabolism, pathology*, radiotherapy Humans Immunoenzyme Techniques Immunoprecipitation In Situ Nick-End Labeling Inhibitor of Apoptosis Proteins / genetics, metabolism Mice Mice, Nude Neoplastic Stem Cells / metabolism*, radiation effects* RNA, Messenger / genetics RNA, Small Interfering / genetics Real-Time Polymerase Chain Reaction Receptors, Urokinase Plasminogen Activator / antagonists & inhibitors*, genetics, metabolism Reverse Transcriptase Polymerase Chain Reaction Transcription, Genetic |
| Grant Support | |
ID/Acronym/Agency:
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CA116708/CA/NCI NIH HHS; R01 CA116708/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/BIRC5 protein, human; 0/Inhibitor of Apoptosis Proteins; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Receptors, Urokinase Plasminogen Activator; EC 3.4.22.1/Cathepsin B |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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