Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells.
The intracellular signaling pathways that control O(2) deprivation (anoxia)-induced apoptosis have not been fully defined in lung epithelial cells. We show here that the lung epithelial cell line A549 releases cytochrome c and activates caspase-9 followed by DNA fragmentation and plasma membrane breakage in response to anoxia. The antiapoptotic protein Bcl-X(L) prevented the anoxia-induced cell death by inhibiting the release of cytochrome c and caspase-9 activation. A549 cells devoid of mitochondrial DNA (rho(o)-cells) and lacking a functional electron transport chain were resistant to anoxia-induced apoptosis. A549 cells preconditioned with either hypoxia (1.5% O(2)) or tumor necrosis factor-alpha, which activated the transcription factors hypoxia-inducible factor-1 or nuclear factor-kappaB, respectively, did not provide protection from anoxia-induced cell death. These results indicate that A549 cells require a functional electron transport chain and the release of cytochrome c for anoxia-induced apoptosis.
Santore
Matthew T
MT
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Medical School, 300 E Superior Street, Chicago, IL 60601, USA.
McClintock
David S
DS
Lee
Vivian Y
VY
Budinger
G R Scott
GR
Chandel
Navdeep S
NS
D000230:Adenocarcinoma; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008175:Lung Neoplasms; D008928:Mitochondria / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases