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Blood, 1 May 2001, Vol. 97, No. 9, pp. 2830-2838
NEOPLASIA
Regulation of the nuclear proteasome activity in myelomonocytic
human leukemia cells after adriamycin treatment
Özlem Ciftci,
Oliver Ullrich,
Christian A. Schmidt,
Antje Diestel, and
Ralf Hass
From the Department of Cell and Neurobiology, Institute
of Anatomy, and Department of Hematology and Oncology, University
Hospital Charité, Humboldt University, Berlin, Germany; and
Department of Biochemistry and Tumor Biology, Clinic of Obstetrics and
Gynecology, Medical School, Hannover, Germany.
Treatment of different human leukemia cell variants with the
anthracycline adriamycin was associated with a rapid activation of the
proteasome. Thus, proliferating U937, TUR, and retrodifferentiated U937
cells exhibited a 4.3-fold, 5.8-fold, and 4.3-fold proteasome activation within 15 minutes after adriamycin treatment, respectively. In contrast, little if any proteasome activation was detectable in a
growth-arrested differentiated U937 population following adriamycin
treatment. Further analysis of this mechanism revealed a significant
reduction of adriamycin-induced proteasome activity after inhibition of
poly(ADP-ribose) polymerase (PARP) by 3-aminobenzamide (3-ABA) in the
proliferating leukemic cell types. These findings suggested that PARP
is involved in the regulation of drug-induced proteasome activation.
Indeed, anti-PARP immunoprecipitation experiments of adriamycin-treated
cells revealed increasing levels of coprecipitated, enzymatically
active proteasome particularly in the proliferating cell variants in
contrast to the differentiated U937 cells, with a maximum after 15 minutes, and sensitivity to PARP inhibition by 3-ABA. The
specific role of the PARP was investigated in U937 and TUR cell clones
stably transfected with a constitutively active antisense PARP (asPARP)
vector. Thus, asPARP-TUR cells developed a 25-fold increased
sensitivity to adriamycin treatment. Furthermore, we investigated
leukemic blasts isolated from acute myelogenous leukemia patients
and obtained a similarly enhanced proteasome activity after adriamycin
treatment, which was dependent on the PARP and thus could be
coprecipitated with anti-PARP antibodies. Transient transfection of
leukemic blasts with the asPARP vector significantly reduced the
adriamycin-induced proteasome activation. These data suggest that the
PARP-associated nuclear proteasome activation represents a potential
target within chemotherapeutic defense mechanisms developed by leukemia cells.
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