TY - JOUR
T1 - Apoptosis-resistance of hypoxic cells
T2 - Multiple factors involved and a role for IAP-2
AU - Dong, Zheng
AU - Wang, Jin Zhao
AU - Yu, Fushin
AU - Venkatachalam, Manjeri A.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S0002-9440(10)63693-0
DO - 10.1016/S0002-9440(10)63693-0
M3 - Article
C2 - 12875985
AN - SCOPUS:0042845994
SN - 0002-9440
VL - 163
SP - 663
EP - 671
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -