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Blood, 1 April 2001, Vol. 97, No. 7, pp. 2105-2114
NEOPLASIA
Synergistic induction of apoptosis in human leukemia cells (U937)
exposed to bryostatin 1 and the proteasome inhibitor lactacystin
involves dysregulation of the PKC/MAPK cascade
Julie A. Vrana and
Steven Grant
From the Departments of Medicine, Microbiology,
Pharmacology, and Biochemistry, Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA.
Cotreatment with a minimally toxic concentration of the protein
kinase C (PKC) activator (and down-regulator) bryostatin 1 (BRY)
induced a marked increase in mitochondrial dysfunction and apoptosis in
U937 monocytic leukemia cells exposed to the proteasome inhibitor
lactacystin (LC). This effect was blocked by cycloheximide, but not by
 -amanitin or actinomycin D. Qualitatively similar interactions were
observed with other PKC activators (eg, phorbol 12-myristate 13-acetate
and mezerein), but not phospholipase C, which does not down-regulate
the enzyme. These events were examined in relationship to functional
alterations in stress (eg, SAPK, JNK) and survival (eg, MAPK, ERK)
signaling pathways. The observations that LC/BRY treatment failed to
trigger JNK activation and that cell death was unaffected by a
dominant-interfering form of c-JUN (TAM67) or by pretreatment with
either curcumin or the p38/RK inhibitor, SB203580, suggested that the
SAPK pathway was not involved in potentiation of apoptosis. In marked
contrast, perturbations in the PKC/Raf/MAPK pathway played an integral
role in LC/BRY-mediated cell death based on evidence that pretreatment
of cells with bisindolylmaleimide I, a selective PKC inhibitor, or
geldanamycin, a benzoquinone ansamycin, which destabilizes and depletes
Raf-1, markedly suppressed apoptosis. Furthermore, ERK phosphorylation
was substantially prolonged in LC/BRY-treated cells compared to those
exposed to BRY alone, and pretreatment with the highly specific MEK
inhibitors, PD98059, U0126, and SL327, opposed ERK activation while
protecting cells from LC/BRY-induced lethality. Together, these
findings suggest a role for activation and/or dysregulation of the
PKC/MAPK cascade in modulation of leukemic cell apoptosis following
exposure to the proteasome inhibitor LC.
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