Influence of hypoxia on TRAIL-induced apoptosis in tumor cells

Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):386-96. doi: 10.1016/j.ijrobp.2003.09.052.


Purpose: Tumor hypoxia reduces the efficacy of radiotherapy, many types of chemotherapy, and tumor necrosis factor-alpha (TNF-alpha). TRAIL (TNF-alpha-related apoptosis-inducing ligand) is a ligand for death receptors of the TNF superfamily shown to be selectively toxic for tumor cells and thereby a promising antineoplastic tool. The impact of hypoxia on TRAIL-induced apoptosis was examined in this study.

Methods and materials: Apoptosis induction and growth rates of various tumor cell lines under hypoxia were evaluated in vitro. Biologically effective induction of hypoxia was verified by determination of hypoxia-inducible factor-1 (HIF-1) activation. The efficacy of TRAIL- and radiation-induced apoptosis under different oxygen conditions was quantified in vitro. The impact of Bcl-2 on TRAIL-induced apoptosis under hypoxia or normoxia was evaluated by comparing cells expressing Bcl-2 with a vector control.

Results: Moderate hypoxia caused no growth retardation or apoptosis, but led to activation of HIF-1 as a prerequisite of hypoxic gene induction. Cellular responses to TRAIL differed considerably among the cell lines tested. Hypoxia reduced radiation-induced, but not TRAIL-induced, apoptosis in the tested cell lines. Hypoxia did not induce Bcl-2 expression. Bcl-2 had a minor impact on the efficacy of TRAIL-induced apoptosis.

Conclusion: Taken together, the data indicate that TRAIL is clearly effective under conditions of proven hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Caspase 8
  • Caspases / metabolism
  • Cell Hypoxia / physiology*
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / radiation effects
  • Cell Nucleus / metabolism
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Drug Screening Assays, Antitumor
  • Enzyme Activation
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Jurkat Cells / drug effects
  • Jurkat Cells / radiation effects
  • Membrane Glycoproteins / pharmacology*
  • Nuclear Proteins / metabolism*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Transcription Factors*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Glycoproteins
  • Nuclear Proteins
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • DNA
  • CASP8 protein, human
  • Caspase 8
  • Caspases