Cross-talk between NFkB and the PI3-kinase/AKT pathway can be targeted in primary effusion lymphoma (PEL) cell lines for efficient apoptosis

• Published in: PloS one 2012-06, Vol.7 (6), p.e39945
• Main Authors: Hussain, Azhar R, Ahmed, Saeeda O, Ahmed, Maqbool, Khan, Omar S, Al Abdulmohsen, Sally, Platanias, Leonidas C, Al-Kuraya, Khawla S, Uddin, Shahab
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; B-cell lymphoma; Biology; Cancer therapies; Cascades; Caspases - metabolism; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Colorectal cancer; Cytochrome; Down-Regulation - drug effects; Drug dosages; Drug resistance; Drug Synergism; Effusion; Enzyme Activation - drug effects; Enzymes; Gene silencing; Genetic engineering; Hematology; Humans; I-kappa B Proteins - metabolism; Inhibition; Kinases; Lymphocytes B; Lymphoma; Lymphoma, Primary Effusion - enzymology; Lymphoma, Primary Effusion - pathology; Lymphomas; Medicine; Mitochondria - drug effects; Mitochondria - metabolism; Multiple myeloma; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; NF-κB protein; Nitriles - pharmacology; Pathways; Pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Primary effusion lymphoma; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Ribonucleic acid; RNA; RNA-mediated interference; Signal Transduction - drug effects; Signaling; siRNA; Sulfones - pharmacology; Survival; Tumor cell lines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039945

A number of constitutively activated signaling pathways play critical roles in the survival and growth of primary effusion lymphoma cells (PELs) including NFkB and PI3/AKT kinase cascades. NFkBis constitutively activated in a number of malignancies, including multiple myeloma, Burkitt's lymphoma and diffuse large cell B-cell lymphoma. However, its role in primary effusion lymphoma has not been fully explored. We used pharmacological inhibition and gene silencing to define the role of NFkB in growth and survival of PEL cells. Inhibition of NFkB activity by Bay11-7085 resulted in decreased expression of p65 in the nuclear compartment as detected by EMSA assays. In addition, Bay11-7085 treatment caused de-phosphorylation of AKT and its downstream targets suggesting a cross-talk between NFkB and the PI3-kinase/AKT pathway. Importantly, treatment of PEL cells with Bay11-7085 led to inhibition of cell viability and induced apoptosis in a dose dependent manner. Similar apoptotic effects were found when p65 was knocked down using specific small interference RNA. Finally, co-treatment of PEL cells with suboptimal doses of Bay11-7085 and LY294002 led to synergistic apoptotic responses in PEL cells. These data support a strong biological-link between NFkB and the PI3-kinase/AKT pathway in the modulation of anti-apoptotic effects in PEL cells. Synergistic targeting of these pathways using NFKB- and PI3-kinase/AKT-inhibitors may have a therapeutic potential for the treatment of PEL and possibly other malignancies with constitutive activation of these pathways.