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Vol. 289, Issue 2, 781-790, May 1999
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research
Institute, and Department of Biochemistry and Molecular Biology,
College of Medicine, University of South Florida, Tampa, Florida
(Q.P.D.); and
Department of Pharmacology, University of Pittsburgh
School of Medicine, and University of Pittsburgh Cancer Institute,
Pittsburgh, Pennsylvania (Q.P.D., T.F.M., Y.P., B.A.)
The chimeric oncogene bcr-abl is detected in virtually
every case of chronic myelogenous leukemia. It has been shown that cells (such as K562) expressing Bcr-Abl/p210, a protein tyrosine kinase, not only undergo cellular transformation but also demonstrate multiple drug resistance. Recent studies also demonstrate that the
proteasome is involved in the survival signaling pathway(s). In the
current study, we tested the hypothesis that the proteasome might play
a role in regulating Bcr-Abl function. We have demonstrated by using a
variety of inhibitors that inhibition of the proteasome, but not of the
cysteine protease, activity is able to activate the apoptotic cell
death program in K562 cells. Proteasome inhibition-induced apoptosis is
demonstrated by condensation and fragmentation of nuclei, appearance of
an apoptotic population with sub-G1 DNA content, the
internucleosomal fragmentation of DNA, and cleavage of poly(ADP-ribose)
polymerase, and can be blocked by a specific caspase-3-like
tetrapeptide inhibitor. Western blot analysis with specific antibodies
to c-Abl and Bcr proteins show that treatment of K562 cells with a
proteasome inhibitor results in significant reduction of Bcr-Abl
protein expression, which occurs several hours before the onset of
apoptotic execution. Levels of c-Abl/p145 and Bcr/p160 proteins,
however, remain essentially unaltered at that time. Furthermore,
reduced Bcr-Abl expression is reflected in significantly attenuated
Bcr-Abl-mediated protein tyrosine phosphorylation. Taken together,
these results indicate that proteasome inhibition is sufficient to
inactivate Bcr-Abl function and subsequently activate the apoptotic
death program in cells that are resistant to apoptosis induced by chemotherapy.
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