| Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells. | |
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MedLine Citation:
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PMID: 22076676 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glioma cancer cells adapt to changing microenvironment and shift from mitochondrial oxidative phosphorylation to aerobic glycolysis for their metabolic needs irrespective of oxygen availability. In the present study, we show that silencing MMP-9 in combination with uPAR/cathepsin B switch the glycolytic metabolism of glioma cells to oxidative phosphorylation (OXPHOS) and generate reactive oxygen species (ROS) to predispose glioma cells to mitochondrial outer membrane permeabilization. shRNA for MMP-9 and uPAR (pMU) as well as shRNA for MMP-9 and cathepsin B (pMC) activated complexes of mitochondria involved in OXPHOS and inhibited glycolytic hexokinase expression. The decreased interaction of hexokinase 2 with mitochondria in the treated cells indicated the inhibition of glycolysis activation. Overexpression of Akt reversed the pMU- and pMC-mediated OXPHOS to glycolysis switch. The OXPHOS un-coupler oligomycin A altered the expression levels of the Bcl-2 family of proteins; treatment with pMU or pMC reversed this effect and induced mitochondrial outer membrane permeabilization. In addition, our results show changes in mitochondrial pore transition to release cytochrome c due to changes in the VDAC-Bcl-XL and BAX-BAK interaction with pMU and pMC treatments. Taken together, our results suggest that pMU and pMC treatments switch glioma cells from the glycolytic to the OXPHOS pathway through an inhibitory effect on Akt, ROS induction and an increase of cytosolic cytochrome c accumulation. These results demonstrate the potential of pMU and pMC as therapeutic candidates for the treatment of glioma. |
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Authors:
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Shivani Ponnala; Chandramu Chetty; Krishna Kumar Veeravalli; Dzung H Dinh; Jeffrey D Klopfenstein; Jasti S Rao |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-11-07 |
Journal Detail:
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Title: International journal of oncology Volume: 40 ISSN: 1791-2423 ISO Abbreviation: Int. J. Oncol. Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2011-12-06 Completed Date: 2012-04-06 Revised Date: 2013-04-08 |
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: 509-18 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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Antineoplastic Agents
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pharmacology Apoptosis Apoptosis Regulatory Proteins / metabolism Cathepsin B / genetics, metabolism Cell Line, Tumor / drug effects Cell Survival / drug effects Electron Transport Chain Complex Proteins / metabolism Gene Knockdown Techniques Glioma / metabolism* Glycolysis Humans Matrix Metalloproteinase 9 / genetics, metabolism Mitochondrial Membranes / metabolism* Oxidative Phosphorylation Permeability Protein Processing, Post-Translational RNA Interference RNA, Small Interfering / pharmacology Receptors, Urokinase Plasminogen Activator / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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NS047699/NS/NINDS NIH HHS; R01 NS047699-07/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/Electron Transport Chain Complex Proteins; 0/RNA, Small Interfering; 0/Receptors, Urokinase Plasminogen Activator; EC 3.4.22.1/CTSB protein, human; EC 3.4.22.1/Cathepsin B; 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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