title: Metabolic remodeling precedes mitochondrial outer membrane permeabilization             in human glioma xenograft cells.
abstract: 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.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of                     Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
authors.forename: Shivani
authors.initials: S
authors.lastname: Ponnala
authors.forename: Chandramu
authors.initials: C
authors.lastname: Chetty
authors.forename: Krishna Kumar
authors.initials: KK
authors.lastname: Veeravalli
authors.forename: Dzung H
authors.initials: DH
authors.lastname: Dinh
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Klopfenstein
authors.forename: Jasti S
authors.initials: JS
authors.lastname: Rao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010539:Permeability; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D045222:Electron Transport Chain Complex Proteins; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; C533912:CTSB protein, human; D002401:Cathepsin B; D020780:Matrix Metalloproteinase 9
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