Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells

Am J Physiol Lung Cell Mol Physiol. 2002 Apr;282(4):L727-34. doi: 10.1152/ajplung.00281.2001.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 9
  • Caspases / metabolism
  • Cytochrome c Group / metabolism
  • DNA-Binding Proteins / metabolism
  • Electron Transport / physiology
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Humans
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lung Neoplasms
  • Mitochondria / enzymology*
  • NF-kappa B / metabolism
  • Nuclear Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism
  • Transcription Factors*
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology
  • bcl-X Protein

Substances

  • Antineoplastic Agents
  • BCL2L1 protein, human
  • Cytochrome c Group
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NF-kappa B
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • bcl-X Protein
  • CASP9 protein, human
  • Caspase 9
  • Caspases