Kim SW, Oleksyn DW, Rossi RM et al.Protein kinase C-associated kinase is required for NF-kappaB signaling and survival in diffuse large B-cell lymphoma cells. Blood 111:1644-1653

University of Rochester, Rochester, New York, United States
Blood (Impact Factor: 10.45). 03/2008; 111(3):1644-53. DOI: 10.1182/blood-2007-05-088591
Source: PubMed


Diffuse large B-cell lymphoma (DLBCL) is an aggressive and the most common type of non-Hodgkin lymphoma. Despite recent advances in treatment, less than 50% of the patients are cured with current multiagent chemotherapy. Abnormal NF-kappaB activity not only contributes to tumor development but also renders cancer cells resistant to chemotherapeutic agents. Identifying and targeting signaling molecules that control NF-kappaB activation in cancer cells may thus yield more effective therapy for DLBCL. Here, we show that while overexpression of protein kinase C-associated kinase (PKK) activates NF-kappaB signaling in DLBCL cells, suppression of PKK expression inhibits NF-kappaB activity in these cells. In addition, we show that NF-kappaB activation induced by B cell-activating factor of tumor necrosis factor family (BAFF) in DLBCL cells requires PKK. Importantly, we show that knockdown of PKK impairs the survival of DLBCL cells in vitro and inhibits tumor growth of xenografted DLBCL cells in mice. Suppression of PKK expression also sensitizes DLBCL cells to treatment with chemotherapeutic agents. Together, these results indicate that PKK plays a pivotal role in the survival of human DLBCL cells and represents a potential target for DLBCL therapy.

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Available from: Randall Rossi, Jan 07, 2015
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    • "The NFkB survival pathway has been found to be constitutively activated in various cancer cells [29], [30], [31], but its role in PEL cells is unknown. We examined the activation of status of NFkB in different PEL cell lines. "
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    • "RNA interference screens have demonstrated that CARD11 , BCL10 and MALT1 , molecules that may cooperate to transduce NF - jB - activating signals from the BCR , are essential for NF - jB activation and cell survival in ABC - DLBCL - like cell lines , implicating the BCR signalling pathway as a key regulator of NF - jB in ABC - DLBCL ( Ngo et al , 2006 ) . Most recently , protein kinase C - associated kinase , a signalling molecule that functions to link protein kinase C and NF - jB , has been implicated in DLBCL ; ablation of this signalling molecule inhibits NF - jB activity , decreases NF - jB target gene expression , induces apoptosis and decreases tumour growth in vivo in ABC - DLBCL - like cells ( Kim et al , 2008 ) . Primary mediastinal B - cell lymphoma ( PMBL ) is a clinically distinct subset of DLBCL which is thought to arise from thymic B cells and has a relatively good prognosis compared to ABC - DLBCL . "
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    ABSTRACT: Nuclear Factor kappaB (NF-kappaB) transcription factors are central regulators of lymphocyte proliferation, survival and development. Although normally subject to tight control, constitutive activation of NF-kappaB promotes inappropriate lymphocyte survival and proliferation, and is recognised as key pathological feature in various lymphoid malignancies. Inhibition of NF-kappaB may be an attractive therapeutic approach in these diseases. This review focuses on the mechanisms and functional consequences of NF-kappaB activation in lymphoid malignancies and potential therapeutic strategies for inhibition of NF-kappaB.
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