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Inhibition of proteasome function induces programmed cell death in proliferating endothelial cells
H C Drexler1, W Risau, M A Konerding
1Max Planck Institut für physiologische und klinische Forschung, Abt. Molekulare Zellbiologie, 61231 Bad Nauheim, Germany. drexler@kerckhoff.mpg.de
Summary
Proteasome inhibitors like PSI induce apoptosis in proliferating endothelial cells at low doses, but require much higher doses for quiescent cells. This suggests potential anti-angiogenic and anti-neoplastic applications.
Area of Science:
- Cell Biology
- Biochemistry
- Pharmacology
Background:
- The ubiquitin-proteasome system regulates programmed cell death.
- Proteasomal activity is crucial for cell viability and proliferation.
Purpose of the Study:
- To investigate the differential effects of proteasome inhibitors on endothelial cell viability.
- To explore the potential of proteasome inhibitors as anti-angiogenic and anti-neoplastic agents.
Main Methods:
- In vitro studies using primary endothelial cells (proliferating vs. quiescent).
- In vivo studies using the embryonic chick chorioallantoic membrane (CAM) model.
- Assessment of apoptosis induction and cell death pathways.
Main Results:
- Proteasome inhibitor PSI induced apoptosis in proliferating endothelial cells at nanomolar concentrations.
- Quiescent endothelial cells required 340-fold higher PSI concentrations for apoptosis induction.
- PSI-induced cell death involved caspase-3 activation.
- In vivo, PSI treatment of CAM led to endothelial cell apoptosis, vascular collapse, and reduced blood flow.
Conclusions:
- Endothelial cell proliferation status significantly influences sensitivity to proteasome inhibitors.
- Proteasome inhibitors demonstrate potent anti-angiogenic effects in vivo.
- PSI exhibits potential as a novel anti-angiogenic and anti-neoplastic therapeutic agent.