title: GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death.
abstract: 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.
authors: Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire C3M, équipe 'contrôle métabolique des morts cellulaires', Nice, France.
authors: M A
authors: MA
authors: Jacquin
authors: J
authors: J
authors: Chiche
authors: B
authors: B
authors: Zunino
authors: M
authors: M
authors: Bénéteau
authors: O
authors: O
authors: Meynet
authors: L A
authors: LA
authors: Pradelli
authors: S
authors: S
authors: Marchetti
authors: A
authors: A
authors: Cornille
authors: M
authors: M
authors: Carles
authors: J-E
authors: JE
authors: Ricci
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D010735:Phosphoglycerate Kinase / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; D051020:bcl-X Protein; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D051057:Proto-Oncogene Proteins c-akt; D010735:Phosphoglycerate Kinase; D020169:Caspases; D010751:Phosphopyruvate Hydratase
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