Abstract
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-X(L), 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-X(L) 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.
Highlights
Under hypoxia, some cells are irreversibly injured and die, whereas others can adapt to the stress and survive
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
Hypoxia-selected cells are cross-resistant to cell injury and death induced by different types of insults
Summary
The selected cells are cross-resistant to apoptosis induced by staurosporine, azide, and cisplatin These cells up-regulate Bcl-XL, an anti-apoptotic protein. Some cells die because of oxygen deficiency, other tumor cells survive the stress and adapt to the hypoxic microenvironment. These cells become more aggressive and resistant to cell death during cancer therapy (9 –12). Hypoxia-selected cells are cross-resistant to cell injury and death induced by different types of insults These cells upregulate Bcl-XL, which interacts with the pro-apoptotic molecule Bax and abrogates its toxicity in mitochondria, resulting in the preservation of mitochondrial integrity, cytochrome c (Cyt c) and cell viability. Bcl-XL plays a critical role in hypoxia-selection of death resistance
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