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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-02-0539.
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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3741-3748
NEOPLASIA
Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is
involved in the defect of apoptosis in B-CLL: association with protein
kinase C
Ingo Ringshausen,
Folker Schneller,
Christian Bogner,
Susanne Hipp,
Justus Duyster,
Christian Peschel, and
Thomas Decker
From the Third Department of Medicine, Technical
University of Munich, Germany.
In the present study we analyzed the role of phophatidylinositol-3
kinase (PI-3K) in B chronic lymphocytic leukemia (B-CLL) cells.
PI-3K is activated by many stimuli and is linked to several different signaling pathways. We demonstrated that inhibition of PI-3K
by a specific inhibitor, LY294002, induced apoptosis in B-CLL cells in
vitro. This effect was specific for the inhibition of PI-3K because
inhibition of other signaling pathways such as extracellular
signaling-regulated kinase (ERK), p38, or p70S6 kinase did not affect
spontaneous apoptosis. Furthermore, PI-3K was constitutively activated
in freshly isolated B-CLL cells. Corresponding to enhanced
apoptosis, LY294002 down-regulated expression of the antiapoptotic
proteins X-linked inhibitor of apoptosis protein (XIAP) and
Mcl-1. Next, we investigated which factors downstream of PI-3K were
activated in B-CLL cells. We demonstrated that protein kinase B/Akt is
expressed in all tested CLL samples but no activation of Akt was
detected. In contrast, we observed a constitutive activation of protein
kinase C (PKC) in freshly isolated B-CLL cells. PKC is linked
to PI-3K and is phosphorylated at Thr505 in response to PI-3K
activation. We further demonstrated that tyrosine phosphorylation and
activity of PKC were dependent on PI-3K activity in B-CLL cells.
Inhibition of PKC by the specific inhibitor Rottlerin
strikingly enhanced apoptosis. In contrast, peripheral blood B cells of
healthy donors were resistant to inhibition of PI-3K or PKC. We
conclude that activated PI-3K might be important in the pathogenesis of
B-CLL, and survival signals might be mediated via PKC. Therefore,
inhibition of PI-3K or PKC may be an innovative approach to treat
B-CLL.
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