Essential role of TAK1 in regulating mantle cell lymphoma survival.

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.

• Authors: Daniela Buglio, Sangeetha Palakurthi, Kate Byth, Francisco Vega, Dorin Toader, Jamal Saeh, Sattva S Neelapu, Anas Younes
• Journal: Blood (Blood) Vol. 120 Issue 2 Pg. 347-55 (Jul 12 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22649101 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Protein Kinase Inhibitors
• RNA, Small Interfering
• NF-KappaB Inhibitor alpha
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Apoptosis
• Cell Line, Tumor
• Cell Survival (genetics, physiology)
• Hodgkin Disease (enzymology, genetics, pathology)
• Humans
• I-kappa B Proteins (metabolism)
• Lymphoma, Large-Cell, Anaplastic (enzymology, genetics, pathology)
• Lymphoma, Mantle-Cell (drug therapy, enzymology, genetics, pathology)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, chemistry, genetics, physiology)
• Models, Molecular
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Phosphorylation
• Protein Kinase Inhibitors (chemistry, pharmacology)
• RNA, Small Interfering (genetics)
• p38 Mitogen-Activated Protein Kinases (metabolism)