Involvement of protein kinase C and phosphatidylinositol 3–kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells

• DOI: 10.1182/blood.v99.8.2969
• Publication Date: 2002-10-11T18:33:52Z
• Authors: Montserrat Barragán; Beatriz Bellosillo; Clara Campàs; Dolors Colomer; Gabriel Pons; Joan Gil
• Keywords: Aged, 80 and over; Male; 0301 basic medicine; Cell Survival; Middle Aged; Leukemia, Lymphocytic, Chronic, B-Cell; 3. Good health; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Tumor Cells, Cultured; Humans; Tetradecanoylphorbol Acetate; Female; Interleukin-4; Enzyme Inhibitors; Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase C; Aged; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction

AbstractB-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.