PT  - JOURNAL ARTICLE
AU  - Uddin, Shahab
AU  - Hussain, Azhar R.
AU  - Al-Hussein, Khaled A.
AU  - Manogaran, Pulicat S.
AU  - Wickrema, Amitha
AU  - Gutierrez, Marina I.
AU  - Bhatia, Kishor G.
TI  - Inhibition of Phosphatidylinositol 3′-Kinase/AKT Signaling Promotes Apoptosis of Primary Effusion Lymphoma Cells
AID  - 10.1158/1078-0432.CCR-04-1857
DP  - 2005 Apr 15
TA  - Clinical Cancer Research
PG  - 3102--3108
VI  - 11
IP  - 8
4099  - http://clincancerres.aacrjournals.org/content/11/8/3102.short
4100  - http://clincancerres.aacrjournals.org/content/11/8/3102.full
SO  - Clin Cancer Res2005 Apr 15; 11
AB  - 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.