GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death

Increased glucose catabolism and resistance to cell death are hallmarks of cancers, but the link between them remains elusive. Remarkably, under conditions where caspases are inhibited, the process of cell death is delayed but rarely blocked, leading to the occurrence of caspase-independent cell dea...

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Bibliographic Details
Published in:Cell death and differentiation 2013-08, Vol.20 (8), p.1043-1054
Main Authors: Jacquin, M A, Chiche, J, Zunino, B, Bénéteau, M, Meynet, O, Pradelli, L A, Marchetti, S, Cornille, A, Carles, M, Ricci, J-E
Format: Article
Language:English
Subjects:
631/67/1059/2326
631/80/82
631/80/86
Apoptosis
Apoptosis - physiology
bcl-X Protein - metabolism
Biochemistry
Biomedical and Life Sciences
Caspases - physiology
Cell Biology
Cell Cycle Analysis
Cell death
Cell Death - physiology
Cell Line, Tumor
Cell Survival - physiology
Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) - metabolism
HEK293 Cells
HeLa Cells
Humans
Life Sciences
Mitochondria - physiology
Original Paper
Phosphoglycerate Kinase - physiology
Phosphopyruvate Hydratase - physiology
Protein Binding - physiology
Proto-Oncogene Proteins c-akt - metabolism
Stem Cells
Up-Regulation - physiology
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Summary:Increased glucose catabolism and resistance to cell death are hallmarks of cancers, but the link between them remains elusive. Remarkably, under conditions where caspases are inhibited, the process of cell death is delayed but rarely blocked, leading to the occurrence of caspase-independent cell death (CICD). Escape from CICD is particularly relevant in the context of cancer as apoptosis inhibition only is often not sufficient to allow oncogenic transformation. While most glycolytic enzymes are overexpressed in tumors, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest as it can allow cells to recover from CICD. Here, we show that GAPDH, but no other glycolytic enzymes tested, when overexpressed could bind to active Akt and limit its dephosphorylation. Active Akt prevents FoxO nuclear localization, which precludes Bcl-6 expression and leads to Bcl-xL overexpression. The GAPDH-dependent Bcl-xL overexpression is able to protect a subset of mitochondria from permeabilization that are required for cellular survival from CICD. Thus, our work suggests that GAPDH overexpression could induce Bcl-xL overexpression and protect cells from CICD-induced chemotherapy through preservation of intact mitochondria that may facilitate tumor survival and chemotherapeutic resistance.
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2013.32