Apoptosis-resistance of hypoxic cells: multiple factors involved and a role for IAP-2.
Hypoxia is an important pathogenic factor in ischemic disease and tumorigenesis. Under hypoxia, some cells are irreversibly damaged, whereas others adapt to the stress and may become more resistant to injury. The mechanism underlying such adaptive responses is unclear. Our recent study showed hypoxic induction of inhibitor of apoptosis protein-2 (IAP-2). Here we have investigated the critical steps in the apoptotic cascade that are affected by hypoxia and have identified a role for IAP-2 in apoptosis resistance of hypoxic cells. The results show that cells cultured in hypoxia became resistant to staurosporine-induced apoptosis. Apoptosis resistance of these cells took place at the mitochondria and in the cytosol. At the mitochondrial level, membrane accumulation of the proapoptotic molecule Bax was suppressed. This was accompanied by less cytochrome c (cyt. c) release from the organelles. In the cytosol, hypoxia induced IAP-2; the cytosol with IAP-2 was resistant to cyt. c-stimulated caspase activation. Of significance, immunodepletion of IAP-2 from the hypoxic cytosol restored its competence for caspase activation. Thus, death resistance of hypoxic cells involves multiple factors targeting different stages of apoptosis, with IAP-2 suppressing caspases in the cytosol.
Dong
Zheng
Z
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912, USA. zdong@mail.mcg.edu
Wang
Jin Zhao
JZ
Yu
Fushin
F
Venkatachalam
Manjeri A
MA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002458:Cell Fractionation; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins; D007684:Kidney Tubules / Q000166:cytology; D008928:Mitochondria / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D019311:Staurosporine / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D051034:Inhibitor of Apoptosis Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins; D051028:bcl-2-Associated X Protein; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D000255:Adenosine Triphosphate; D020169:Caspases; D019311:Staurosporine; D005947:Glucose