Essential role of TAK1 in regulating mantle cell lymphoma survival.
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.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Daniela
D
Buglio
Sangeetha
S
Palakurthi
Kate
K
Byth
Francisco
F
Vega
Dorin
D
Toader
Jamal
J
Saeh
Sattva S
SS
Neelapu
Anas
A
Younes
D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D006689:Hodgkin Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008958:Models, Molecular; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D020672:I-kappa B Proteins; D020930:MAP Kinase Kinase Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C000606204:NFKBIA protein, human