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Proteasome inhibitor-induced apoptosis of glioma cells involves the processing of multiple caspases and cytochrome c

B Wagenknecht1, M Hermisson, P Groscurth

  • 1Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Tübingen, Germany.

Journal of Neurochemistry
|November 18, 2000
PubMed

Insights

Proteasome inhibitors induce apoptosis in malignant glioma cells via caspase activation and mitochondrial pathways. This cell death is regulated by Bcl-2, XIAP, and caspase activity, but not death ligand signaling.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The proteasome is crucial for intracellular protein degradation in eukaryotes.
  • Malignant gliomas are aggressive brain tumors with limited treatment options.

Purpose of the Study:

  • To investigate the mechanisms of apoptosis induced by proteasome inhibitors in human malignant glioma cells.
  • To elucidate the role of caspases, Bcl-2, XIAP, and mitochondrial pathways in this process.

Main Methods:

  • Treatment of human malignant glioma cells with proteasome inhibitors (MG132, lactacystin).
  • Assessment of apoptosis using caspase activation, morphological changes, and mitochondrial membrane potential.
  • Inhibition studies using ectopic expression of XIAP and Bcl-2, and caspase inhibitors (zVAD-fmk, crm-A).

Main Results:

  • Proteasome inhibitors trigger apoptosis involving caspases 2, 3, 7, 8, and 9.
  • Apoptosis is inhibited by XIAP, Bcl-2, and cycloheximide, but not by crm-A.
  • Cytochrome c release and mitochondrial membrane potential disruption are key events, with Bcl-2 being a potent inhibitor.
  • Specific morphological alterations are independent of broad-spectrum caspase inhibition.

Conclusions:

  • Proteasome inhibition induces apoptosis in malignant glioma cells through caspase-dependent and mitochondrial pathways.
  • Bcl-2 and XIAP play significant roles in regulating this apoptotic process.
  • Cytochrome c release occurs upstream of XIAP- and crm-A-sensitive caspases, suggesting a complex regulatory network.

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