TY - JOUR
T1 - Hypoxia selection of death-resistant cells
T2 - A role for Bcl-XL
AU - Dong, Zheng
AU - Wang, Jinzhao
PY - 2004/3/5
Y1 - 2004/3/5
N2 - Under hypoxia, some cells are irreversibly injured and die, whereas others can adapt to the stress and survive. The molecular and genetic basis underlying cellular sensitivity to hypoxic injury is unclear. Here we have selected death-resistant cells by repeated episodes of hypoxia. The selected cells are cross-resistant to apoptosis induced by staurosporine, azide, and cisplatin. These cells up-regulate Bcl-XL, an anti-apoptotic protein. Bcl-X L interacts with the pro-apoptotic molecule Bax and abrogates its toxicity in mitochondria, resulting in the preservation of mitochondrial integrity, cytochrome c, and cell viability. Down-regulation of Bcl-X L by antisense oligonucleotides or the newly identified Bcl-X L inhibitor chelerythrine restores cellular sensitivity to injury and death. Thus, Bcl-XL is a key molecule for hypoxia selection of death resistance. These findings may have important implications for the development of solid tumors where hypoxia selects for death-resistant cells that are inert to cancer therapy.
AB - Under hypoxia, some cells are irreversibly injured and die, whereas others can adapt to the stress and survive. The molecular and genetic basis underlying cellular sensitivity to hypoxic injury is unclear. Here we have selected death-resistant cells by repeated episodes of hypoxia. The selected cells are cross-resistant to apoptosis induced by staurosporine, azide, and cisplatin. These cells up-regulate Bcl-XL, an anti-apoptotic protein. Bcl-X L interacts with the pro-apoptotic molecule Bax and abrogates its toxicity in mitochondria, resulting in the preservation of mitochondrial integrity, cytochrome c, and cell viability. Down-regulation of Bcl-X L by antisense oligonucleotides or the newly identified Bcl-X L inhibitor chelerythrine restores cellular sensitivity to injury and death. Thus, Bcl-XL is a key molecule for hypoxia selection of death resistance. These findings may have important implications for the development of solid tumors where hypoxia selects for death-resistant cells that are inert to cancer therapy.
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U2 - 10.1074/jbc.M312225200
DO - 10.1074/jbc.M312225200
M3 - Article
C2 - 14676192
AN - SCOPUS:1542305379
SN - 0021-9258
VL - 279
SP - 9215
EP - 9221
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -