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

• Published in: Clinical cancer research Vol. 11; no. 8; pp. 3102 - 3108
• Main Authors: UDDIN, Shahab, HUSSAIN, Azhar R, AL-HUSSEIN, Khaled A, MANOGARAN, Pulicat S, WICKREMA, Amitha, GUTIERREZ, Marina I, BHATIA, Kishor G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-04-2005
• Subjects: AKT/PKB; Antibodies, Monoclonal - pharmacology; Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; caspases; Cell Line, Tumor; Chromones - pharmacology; cytochrome; Cytochromes c - secretion; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; fas Receptor - immunology; Flow Cytometry - methods; Forkhead Box Protein O1; Forkhead Transcription Factors; Glycogen Synthase Kinase 3 - metabolism; Hematologic and hematopoietic diseases; Humans; Immunoblotting; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma - enzymology; Lymphoma - pathology; Medical sciences; Mitochondria - drug effects; Mitochondria - metabolism; Morpholines - pharmacology; NHL; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Pleural Effusion, Malignant - enzymology; Pleural Effusion, Malignant - pathology; Pleural Effusion, Malignant - physiopathology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Signal Transduction - drug effects; Time Factors; Transcription Factors - metabolism; X-Linked Inhibitor of Apoptosis Protein; Protein kinase B; Enzyme; Transferases; Akt protein kinase; Malignant hemopathy; Non Hodgkin lymphoma; In vitro; 1-Phosphatidylinositol 3-kinase; Signal transduction; Signaling pathway; Cell death; Lymphoproliferative syndrome; Inhibitor; Primary effusion lymphoma; Apoptosis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-1857

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.