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Inhibition of Phosphatidylinositol 3'-Kinase/AKT Signaling Promotes Apoptosis of Primary Effusion Lymphoma Cells

Authors' Affiliations: ¹ King Fahad National Center for Children's Cancer and Research, ² Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; and ³ Section of Hematology-Oncology, University of Chicago, Chicago, Illinois

Requests for reprints: Shahab Uddin, King Fahad National Center for Children's Cancer and Research, MBC #98-16, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Phone: 966-1-2294444, ext. 51815; Fax: 966-1-2293671; E-mail: shahab{at}kfshrc.edu.sa.

Purpose: Phosphatidylinositol 3'-kinase (PI3'-kinase) can be activated by the K1 protein of Kaposi sarcoma–associated herpes virus (KSHV). However, the role of PI3'-kinase in KSHV-associated primary effusion lymphoma (PEL) is not known. To assess this, we studied survival and apoptosis in PEL cell lines following inhibition of PI3'-kinase.

Experimental Design: Constitutive activation of several targets of PI3-kinase and apoptotic proteins were determined by Western blot analysis using specific antibodies. We used LY294002 to block PI3'-kinase/AKT activation and assess apoptosis by flow cytometric analysis.

Results: Blocking PI3'-kinase induced apoptosis in PEL cells, including BC1, BC3, BCBL1, and HBL6, whereas BCP1 was refractory to LY294002-induced apoptosis. LY294002-induced apoptosis did not seem to involve Fas/Fas-L but had an additive effect to CH11-mediated apoptosis. We also show that AKT/PKB is constitutively activated in all PELs and treatment with LY294002 causes complete dephosphorylation in all cell lines except BCP1 where a residual AKT phosphorylation remained after 24 hours of treatment. FKHR and GSK3 were also constitutively phosphorylated in PELs and treatment with LY294002 caused their dephosphorylation. Although inhibition of PI3'-kinase induced cleavage of BID in all cell lines, cytochrome c was released from the mitochondria and caspase-9 and caspase-3 were activated in LY294002-induced apoptotic BC1 but not in resistant BCP1. Similarly, XIAP, a target of AKT, was down-regulated after LY294002 treatment only in sensitive PEL cells.

Conclusions: Our data show that the PI3'-kinase pathway plays a major role in survival of PEL cells and suggest that this cascade may be a promising target for therapeutic intervention in primary effusion lymphomas.

Key Words: NHL • AKT/PKB • cytochrome c • Apoptosis • caspases

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