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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2969-2976
NEOPLASIA
Involvement of protein kinase C and phosphatidylinositol
3-kinase pathways in the survival of B-cell chronic lymphocytic
leukemia cells
Montserrat Barragán,
Beatriz Bellosillo,
Clara Campàs,
Dolors Colomer,
Gabriel Pons, and
Joan Gil
From Unitat de Bioquímica, Departament de
Ciències Fisiol iques II, Universitat de Barcelona, and
Unitat d'Hematopatologia, Servei d'Hematologia, Institut
d'Investigacions Biomèdiques August Pi i Sunyer, Hospital
Clínic, Barcelona, Spain.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the
accumulation of long-lived CD5+ B lymphocytes. TPA
(12-O-tetradecanoylphorbol 13- acetate) and interleukin-4
(IL-4) inhibit apoptosis of B-CLL lymphocytes ex vivo. We used specific
inhibitors of protein kinase C (PKC), extracellular-regulated kinase
(ERK), and phosphatidylinositol 3-kinase (PI3-kinase) to study their
involvement in TPA- and IL-4-induced survival of B-CLL lymphocytes.
BisI, a specific inhibitor of PKC, induced apoptosis and inhibited the
antiapoptotic activity of TPA and IL-4. B-CLL cells have a basal PKC
activity that was increased by TPA but not by IL-4. TPA, but not IL-4,
induced ERK activation. However, the inhibition of ERK activation did
not affect the viability of B-CLL lymphocytes, demonstrating that this
pathway is not involved in their survival. Inhibition of PI3-kinase by
LY294002 induced apoptosis of B-CLL cells and inhibited the survival
effect of IL-4 and TPA. In addition, Akt, a downstream effector of
PI3-kinase activity, was phosphorylated by TPA and IL-4 in B-CLL cells,
though PI3-kinase had no effect on PKC-dependent phosphorylation of
Akt. Furthermore, the inhibition of PKC or PI3-kinase increased
dexamethasone- and fludarabine-induced apoptosis ex vivo in the
presence of survival factors. These results demonstrate that PKC and
PI3-kinase are involved in the survival of B-CLL cells and suggest that
inhibitors of these pathways could be combined with the drugs used in
the treatment of B-CLL.
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