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J. Biol. Chem., Vol. 279, Issue 10, 9215-9221, March 5, 2004

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Hypoxia Selection of Death-resistant Cells

A ROLE FOR Bcl-X_L^*

Zheng Dong, A Carl W. Gottschalk Research Scholar of the American Society of Nephrology and Jinzhao Wang

From the Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912

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.

Received for publication, November 7, 2003 , and in revised form, December 12, 2003.

^* This work was supported by grants from National Institutes of Health, National Kidney Foundation, and the American Society of Nephrology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd, Augusta, GA 30912. Tel.: 706-721-2825; Fax: 706-721-6120; E-mail: zdong{at}mail.mcg.edu.

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