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.
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.
Gramaglia
D
D
Division of Molecular Oncology, Institute for Cancer Research, University of Torino Medical School, Candiolo, Italy. andrea.rasola@ircc.it
Gentile
A
A
Battaglia
M
M
Ranzato
L
L
Petronilli
V
V
Fassetta
M
M
Bernardi
P
P
Rasola
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects; D002458:Cell Fractionation; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003124:Colorimetry; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D005947:Glucose / Q000032:analysis; D006019:Glycolysis / Q000187:drug effects*; D049452:Green Fluorescent Proteins; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D019344:Lactic Acid / Q000032:analysis; D008164:Luminescent Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects; D009336:Necrosis; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D012235:Rhodamines; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D005456:Fluorescent Dyes; D008164:Luminescent Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012235:Rhodamines; D051020:bcl-X Protein; D049452:Green Fluorescent Proteins; D005576:Colforsin; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D005947:Glucose; C047983:1,9-dideoxyforskolin