Apoptosis-resistance of hypoxic cells: Multiple factors involved and a role for IAP-2

Zheng Dong, Jin Zhao Wang, Fushin Yu, Manjeri A. Venkatachalam

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)663-671
Number of pages9
JournalAmerican Journal of Pathology
Volume163
Issue number2
DOIs
StatePublished - Aug 1 2003

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Inhibitor of Apoptosis Proteins
Cytosol
Apoptosis
Caspases
Staurosporine
Cytochromes c
Organelles
Mental Competency
Cultured Cells
Mitochondria
Carcinogenesis
Hypoxia
Membranes
Wounds and Injuries

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Apoptosis-resistance of hypoxic cells : Multiple factors involved and a role for IAP-2. / Dong, Zheng; Wang, Jin Zhao; Yu, Fushin; Venkatachalam, Manjeri A.

In: American Journal of Pathology, Vol. 163, No. 2, 01.08.2003, p. 663-671.

Research output: Contribution to journalArticle

Dong, Zheng ; Wang, Jin Zhao ; Yu, Fushin ; Venkatachalam, Manjeri A. / Apoptosis-resistance of hypoxic cells : Multiple factors involved and a role for IAP-2. In: American Journal of Pathology. 2003 ; Vol. 163, No. 2. pp. 663-671.
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