Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells
Authors: Krishna Kumar Veeravalli
Jasti S Rao
Chandramu Chetty
Shivani Ponnala
Jeffrey D Klopfenstein
Dzung H Dinh
Journal: International Journal of Oncology (2011)
Discipline: CLINICAL MEDICINE
Keywords: Glioma cancer cells; metabolic shift; MMP-9; uPAR; cathepsin B
Affiliations: Department 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. 

Retracted: Yes

PubPeer comments:
 Figure 6A. Two panels, pMU and pMC in the pAKT 5310 row, appear to show an area of overlap as highlighted in blue. Could the authors please check?  , 
 Fig 1A. I am wondering what went so radically wrong in the loading control that it required this piece of intarsia.  , 
 March 2021 retraction: https: www.spandidos-publications.com 10.3892 ijo.2021.5198  Following the publication of the above paper, we were contacted by the University of Illinois at Chicago, to request the retraction of the above article. Following a formal institutional investigation, the investigation panel concluded that the images in question had falsifying elements. Regarding the above study, the specific allegations that were investigated were that of falsifying elements of Fig. 6A, row 2, columns 2 and 3. Following a review of this paper conducted independently by the Editor of International Journal of Oncology, the Editor concurred with the conclusions of the investigation panel, and therefore the above paper has been retracted from the publication. We also tried to contact the authors, but did not receive a reply. The Editor apologizes to the readership for the inconvenience caused.[the original article was published in International Journal of Oncology 40: 509u2011518, 2012; DOI: 10.3892 ijo.2011.1255] Paper reported to the journal in February 2016. , 
 See also https: retractionwatch.com 2021 03 15 falsifying-elements-prompt-retraction-of-three-more-papers-by-former-peorian-of-the-year ,