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Updated: May 27, 2026
MitoCeption: Transferring Isolated Human MSC Mitochondria to Glioblastoma Stem Cells
Published on: February 22, 2017
Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells
Shivani Ponnala1, Chandramu Chetty, Krishna Kumar Veeravalli
1Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
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.
Insights
Silencing MMP-9 with uPAR or cathepsin B shifts glioma metabolism from glycolysis to oxidative phosphorylation (OXPHOS), inducing cell death. These findings highlight potential new therapies for glioma treatment.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Glioma cells exhibit metabolic plasticity, favoring aerobic glycolysis over oxidative phosphorylation (OXPHOS) regardless of oxygen levels.
- This metabolic shift supports tumor growth and resistance to therapy.
Purpose of the Study:
- To investigate the effect of silencing MMP-9 in combination with uPAR or cathepsin B on glioma cell metabolism.
- To explore the potential of these combined silencing strategies as therapeutic approaches for glioma.
Main Methods:
- ব্যবহার করা হয়েছে short hairpin RNA (shRNA) to silence MMP-9 and uPAR (pMU) or MMP-9 and cathepsin B (pMC) in glioma cells.
- Assessed metabolic shifts by measuring oxidative phosphorylation (OXPHOS) and glycolysis markers.
- Analyzed mitochondrial outer membrane permeabilization and apoptosis-related protein interactions (Bcl-2 family, VDAC, Bcl-XL, BAX, BAK).
- Investigated the role of Akt signaling pathway.
Main Results:
- pMU and pMC treatments successfully switched glioma cell metabolism from glycolysis to OXPHOS.
- These treatments activated mitochondrial OXPHOS complexes and inhibited glycolytic hexokinase expression.
- Silencing induced reactive oxygen species (ROS) production, leading to mitochondrial outer membrane permeabilization and cytochrome c release.
- Overexpression of Akt reversed the metabolic switch, indicating its crucial role.
Conclusions:
- Combined silencing of MMP-9 with uPAR or cathepsin B effectively reprograms glioma cell metabolism towards OXPHOS.
- This metabolic reprogramming, coupled with ROS induction and apoptosis signaling, presents a promising therapeutic strategy for glioma.
- pMU and pMC treatments demonstrate potential as novel therapeutic candidates for glioma.
