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Max Planck Institut für physiologische und klinische Forschung, Abt. Molekulare Zellbiologie, 61231 Bad Nauheim, Germany; and
* Johannes Gutenberg-Universität Mainz, Anatomisches Institut, Makroskopischer Bereich, D-55099 Mainz, Germany
1Correspondence: Max Planck Institut für physiologische und klinische Forschung, Abt. Molekulare Zellbiologie, Parkstr. 1, D-61231 Bad Nauheim, Germany. E-mail: hannes.drexler{at}kerckhoff.mpg.de
Proteolysis mediated by the ubiquitin-proteasome system has been
implicated in the regulation of programmed cell death. Here we
investigated the differential effects of proteasomal inhibitors on the
viability of proliferating and quiescent primary endothelial cells
in vitro and in vivo. Subconfluent,
proliferating cells underwent
carbobenzoxy-L-isoleucyl-
-t-butyl-L-glutamyl-L-alanyl-L-leucinal
(PSI) -induced apoptosis at low concentrations (EC50=24
nM), whereas at least 340-fold higher concentrations of PSI were
necessary to obtain the same effect in confluent, contact-inhibited
cells. PSI-mediated cell death could be blocked by a caspase-3
inhibitor (Ac-DEVD-H), but not by a caspase-1 inhibitor (Ac-YVAD-H),
suggesting that a caspase-3-like enzyme is activated during PSI-induced
apoptosis. When applied to the embryonic chick chorioallantoic
membrane, a rapidly expanding tissue, PSI induced massive apoptosis
also in vivo. PSI treatment of the CAM led to the
formation of areas devoid of blood flow due to the induction of
apoptosis in endothelial and other cells and to the collapse of
capillaries and first order vessels. Our results demonstrate that
proteasomal inhibitors such as PSI may prove effective as novel
anti-angiogenic and anti-neoplastic substances.—Drexler, H. C. A., Risau, W., Konerding, M. A. Inhibition of proteasome
function induces programmed cell death in proliferating endothelial
cells.
Key Words: angiogenesis • proteolysis • cell cycle • p27Kip1
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