| RNAi-mediated downregulation of radiation-induced MMP-9 leads to apoptosis via activation of ERK and Akt in IOMM-Lee cells. | |
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MedLine Citation:
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PMID: 19082492 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Patients afflicted with meningiomas are most often treated with radiation therapy followed by surgical resection. However, resistance to radiation treatment has been well documented among different cancers of the brain. In this study, we demonstrate that the malignant meningioma cells (IOMM-Lee cells) overexpress MMP-9 at both the mRNA and protein levels after radiation treatment. We confirmed an increase in the invasive potential of irradiated cells through spheroid migration and matrigel invasion assays. Knockdown of MMP-9 using an adenoviral siRNA construct blocked MMP-9 expression, reduced the invasive nature of cells, and subsequently led to apoptosis. Western blot analysis revealed the activation of ERK, Akt and Fas as well as a decrease in c-JUN levels. Cleavage of PARP and TUNEL-positive characteristics confirmed apoptotic cell death in Ad-MMP-9 infected cells. Treatment with U0126 and transfection with dominant negative ERK plasmid resulted in the decreased phosphorylation of ERK and Akt. Ectopic expression of HA myr-Akt was found to be associated with an increase in pERK, and treatment with LY294002 was shown to block the phosphorylation of Akt and ERK with the restoration of c-JUN. In conclusion, our data suggest that radiation increases MMP-9 expression and the invasive nature of IOMM-Lee cells, both of which can be reversed with siRNA-mediated downregulation of MMP-9, which leads to ERK and Akt-mediated apoptosis. |
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Authors:
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Venkateswara Rao Gogineni; Odysseas Kargiotis; Jeffrey D Klopfenstein; Meena Gujrati; Dzung H Dinh; Jasti S Rao |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of oncology Volume: 34 ISSN: 1019-6439 ISO Abbreviation: Int. J. Oncol. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2008-12-16 Completed Date: 2009-02-24 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 9306042 Medline TA: Int J Oncol Country: Greece |
Other Details:
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Languages: eng Pagination: 209-18 Citation Subset: IM |
Affiliation:
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Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 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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Adenoviridae Antigens, CD95 / metabolism Apoptosis / physiology, radiation effects* Blotting, Western Cell Movement Cell Proliferation / radiation effects Collagen / metabolism Down-Regulation Drug Combinations Enzyme Activation / radiation effects Enzyme Inhibitors / pharmacology Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors, genetics, metabolism* Humans In Situ Nick-End Labeling JNK Mitogen-Activated Protein Kinases / metabolism Laminin / metabolism Matrix Metalloproteinase 9 / antagonists & inhibitors, genetics, metabolism* Meningeal Neoplasms / genetics, metabolism, pathology* Meningioma / genetics, metabolism, pathology* Plasmids Proteoglycans / metabolism Proto-Oncogene Proteins c-akt / antagonists & inhibitors, genetics, metabolism* RNA Interference* RNA, Small Interfering / pharmacology Spheroids, Cellular Transfection Tumor Cells, Cultured X-Rays |
| Grant Support | |
ID/Acronym/Agency:
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CA 116708/CA/NCI NIH HHS; CA 75557/CA/NCI NIH HHS; CA 92393/CA/NCI NIH HHS; CA 95058/CA/NCI NIH HHS; R01 CA075557-10/CA/NCI NIH HHS; R01 CA092393-04/CA/NCI NIH HHS; R01 CA095058-04/CA/NCI NIH HHS; R01 CA116708-03/CA/NCI NIH HHS; R01 NS047699-04A2/NS/NINDS NIH HHS; R01 NS057529-02/NS/NINDS NIH HHS; R01 NS061835-01/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD95; 0/Drug Combinations; 0/Enzyme Inhibitors; 0/FAS protein, human; 0/Laminin; 0/Proteoglycans; 0/RNA, Small Interfering; 119978-18-6/matrigel; 9007-34-5/Collagen; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 3.4.24.35/Matrix Metalloproteinase 9 |
| Comments/Corrections | |
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