Hypoxia induces apoptosis via two independent pathways in Jurkat cells: differential regulation by glucose.
Glucose uptake and metabolism inhibit hypoxia-induced apoptosis in a variety of cell types, but the underlying molecular mechanisms remain poorly understood. In the present study, we explore hypoxia-mediated cell death pathways in Jurkat cells in the presence and absence of extracellular glucose. In the absence of extracellular glucose, hypoxia caused cytochrome c release, caspase 3 and poly(ADP-ribose)polymerase cleavage, and DNA fragmentation; this apoptotic response was blocked by the caspase 9 inhibitor z-LEHD-FMK. The presence of extracellular glucose during hypoxia prevented cytochrome c release and activation of caspase 9 but did not prevent apoptosis in Jurkat cells. In these conditions, overexpression of the caspase 8 inhibitor v-FLIP prevented hypoxia-mediated cell death. Thus hypoxia can stimulate two apoptotic pathways in Jurkat cells, one dependent on cytochrome c release from mitochondria that is prevented by glucose uptake and metabolism, and the other independent of cytochrome c release and resulting from activation of the death receptor pathway, which is accelerated by glucose uptake and metabolism.
Malhotra
R
R
Department of Internal Medicine, University of Michigan Medical School and Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan 48109, USA.
Lin
Z
Z
Vincenz
C
C
Brosius
F C
FC
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D003574:Cytochrome c Group / Q000037:antagonists & inhibitors / Q000378:metabolism; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000502:physiology; D010940:Plant Proteins / Q000096:biosynthesis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; C096317:E8 protein, Lycopersicon esculentum; D004791:Enzyme Inhibitors; D010940:Plant Proteins; D011065:Poly(ADP-ribose) Polymerases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D005947:Glucose