Abstract
TGF-β-activated kinase 1 (TAK1), a member of the MAPK kinase family, plays a key role in B-cell growth and development. In the present study, we examined the potential role of TAK1 as a therapeutic target for lymphoma. Here, we show that the active phosphorylated form of TAK1 is abundantly expressed in a panel of lymphoma cell lines, including mantle cell, anaplastic large cell, and Hodgkin lymphoma cell lines. Silencing TAK1 expression via the use of siRNA inhibited the activation of NF-κB and p38 and induced apoptosis in lymphoma cell lines. Moreover, submicromolar concentrations of AZ-TAK1, a novel ATP-competitive small molecule inhibitor of TAK1, dephosphorylated TAK1, p38, and IκB-α in lymphoma cell lines. These molecular events were associated with the release of cytochrome c into the cytosol, down-regulation of X-linked inhibitor of apoptosis, activation of caspase 9, and induction of apoptosis. We also demonstrate that primary lymphoma cells express TAK1 and pTAK1 and were sensitive to AZ-TAK1-mediated cell death. Collectively, our data demonstrate an essential role for TAK1 in regulating critical survival mechanisms in lymphoma and suggest that it may serve as a therapeutic target.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Cell Line, Tumor
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Cell Survival / genetics
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Cell Survival / physiology
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Hodgkin Disease / enzymology
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Hodgkin Disease / genetics
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Hodgkin Disease / pathology
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Humans
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I-kappa B Proteins / metabolism
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Lymphoma, Large-Cell, Anaplastic / enzymology
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Lymphoma, Large-Cell, Anaplastic / genetics
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Lymphoma, Large-Cell, Anaplastic / pathology
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Lymphoma, Mantle-Cell / drug therapy
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Lymphoma, Mantle-Cell / enzymology*
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Lymphoma, Mantle-Cell / genetics
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Lymphoma, Mantle-Cell / pathology
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / chemistry
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / physiology*
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Models, Molecular
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism
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Phosphorylation
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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RNA, Small Interfering / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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I-kappa B Proteins
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NF-kappa B
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NFKBIA protein, human
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Protein Kinase Inhibitors
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RNA, Small Interfering
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NF-KappaB Inhibitor alpha
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7