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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Inhibition of phosphatidylinositol 3′-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells
Clinical Cancer Research, Volume 11, No. 8, Year 2005
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Description
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. © 2005 American Association for Cancer Research.
Authors & Co-Authors
Uddin, Shahab
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Hussain, Azhar R.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
al-Hussein, Khalid A.F.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Manogaran, Pulicat Subramanian
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Wickrema, Amitha
United States, Chicago
The University of Chicago
Gutiérrez, Marina Inés
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Bhatia, Kishor G.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Statistics
Citations: 111
Authors: 7
Affiliations: 2
Identifiers
Doi:
10.1158/1078-0432.CCR-04-1857
ISSN:
10780432
Research Areas
Cancer
Study Design
Randomised Control Trial