Document Detail

Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells.
MedLine Citation:
PMID:  22076676     Owner:  NLM     Status:  MEDLINE    
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.
Shivani Ponnala; Chandramu Chetty; Krishna Kumar Veeravalli; Dzung H Dinh; Jeffrey D Klopfenstein; Jasti S Rao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-11-07
Journal Detail:
Title:  International journal of oncology     Volume:  40     ISSN:  1791-2423     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2011-12-06     Completed Date:  2012-04-06     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  509-18     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Agents / pharmacology
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*
Matrix Metalloproteinase 9 / genetics,  metabolism
Mitochondrial Membranes / metabolism*
Oxidative Phosphorylation
Protein Processing, Post-Translational
RNA Interference
RNA, Small Interfering / pharmacology
Receptors, Urokinase Plasminogen Activator / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/Electron Transport Chain Complex Proteins; 0/RNA, Small Interfering; 0/Receptors, Urokinase Plasminogen Activator; EC protein, human; EC B; EC Metalloproteinase 9

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