Apoptosis to necrosis switching downstream of apoptosome formation requires inhibition of both glycolysis and oxidative phosphorylation in a BCL-X(L)- and PKB/AKT-independent fashion.

Abstract	Human T-lymphoma Jurkat cells treated with several intrinsic death stimuli readily undergo a stepwise apoptotic program. Treatment with 1,9-dideoxyforskolin (ddFSK), an inactive analogue of the adenylate cyclase activator forskolin, induces necrotic cell death and switches to necrosis the response to the apoptosis inducers in Jurkat and in other cell models. Yet, in the presence of ddFSK, mitochondrial changes are enhanced and apoptosome formation takes place. We show that ddFSK does not inhibit the catabolic steps of apoptosis, but rather elicits a profound ATP depletion that in turn tunes the mode of cell demise towards necrosis. Treatment with ddFSK impairs both glycolysis and oxidative phosphorylation in a Bcl-X(L)- and PKB/Akt-independent fashion, and inhibition of both processes is needed to affect apoptosis progression. Apoptosis is not blocked per se by ATP depletion, as engagement of the Fas receptor directly activates caspases, thus bypassing ddFSK inhibition.
Authors	D Gramaglia, A Gentile, M Battaglia, L Ranzato, V Petronilli, M Fassetta, P Bernardi, A Rasola
Journal	Cell death and differentiation (Cell Death Differ) Vol. 11 Issue 3 Pg. 342-53 (Mar 2004) ISSN: 1350-9047 [Print] England
PMID	14713956 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	BCL2L1 protein, human Fluorescent Dyes Luminescent Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Rhodamines bcl-X Protein Green Fluorescent Proteins Colforsin Lactic Acid Adenosine Triphosphate AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Caspases Glucose 1,9-dideoxyforskolin
Topics	Adenosine Triphosphate (metabolism) Apoptosis (drug effects) Blotting, Western Caspases (drug effects) Cell Fractionation Colforsin (analogs & derivatives, pharmacology) Colorimetry Dose-Response Relationship, Drug Enzyme Activation (drug effects) Flow Cytometry Fluorescent Dyes Glucose (analysis) Glycolysis (drug effects) Green Fluorescent Proteins Humans Jurkat Cells Kinetics Lactic Acid (analysis) Luminescent Proteins (metabolism) Microscopy, Confocal Mitochondria (drug effects) Necrosis Oxidative Phosphorylation (drug effects) Protein Serine-Threonine Kinases (drug effects, metabolism) Proto-Oncogene Proteins (drug effects, metabolism) Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism) Rhodamines bcl-X Protein

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