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Proteasome inhibitors induce intracellular protein aggregation and cell death by an oxygen-dependent mechanism

Marilene Demasi1, Kelvin J A Davies

  • 1Ethel Percy Andrus Gerontology Center, and Division of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089-0191, USA. mari_masi@hotmail.com

FEBS Letters
|May 6, 2003
PubMed

Insights

Proteasome inhibitors induce oxidative stress and cell death in liver cells, but this effect is significantly reduced under low oxygen conditions, suggesting an oxygen-dependent mechanism.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Toxicology

Background:

  • Proteasome inhibitors are used in cancer therapy but can cause cellular damage.
  • Oxidative stress is implicated in various cellular dysfunctions and diseases.
  • The role of oxygen levels in proteasome inhibitor-induced toxicity is not fully understood.

Purpose of the Study:

  • To investigate the impact of proteasome inhibitors on liver cells under varying oxygen conditions.
  • To elucidate the mechanism behind proteasome inhibitor-induced oxidative protein modifications and cell death.

Main Methods:

  • Clone 9 liver cells were treated with proteasome inhibitors (lactacystin, clastro lactacystin beta-lactone, tri-leucine vinyl sulfone).
  • Cells were incubated under standard (21%) and low (3%) oxygen atmospheres.
  • Oxidative protein modifications (solubility, aggregation, carbonyl formation), cell morphology, and viability were assessed.

Main Results:

  • Proteasome inhibitors induced oxidative protein modifications and reduced cell viability under 21% oxygen.
  • These effects were similar to those caused by hydrogen peroxide treatment.
  • Almost all inhibitor-induced alterations were prevented under 3% oxygen.

Conclusions:

  • Proteasome inhibitor-induced protein oxidation, aggregation, and apoptosis are oxygen-dependent.
  • This suggests a critical role for oxygen in the cellular toxicity of proteasome inhibitors.
  • Manipulating oxygen levels may offer a strategy to mitigate proteasome inhibitor side effects.

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