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Research Articles: Therapeutics, Targets, and Development

Blockade of transforming growth factor-ß-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade

¹ Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama; ² 21st Century COE Program, University of Toyama, Toyama, Japan; and ³ Akira Innate Immunity Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency; ⁴ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

Requests for reprints: Hiroaki Sakurai, Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Phone: 81-76-434-7636; Fax: 81-76-434-5058. E-mail: hsakurai{at}inm.u-toyama.ac.jp

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a member of the TNF- ligand family that selectively induces apoptosis in a variety of tumor cells. To clarify the molecular mechanism of TRAIL-induced apoptosis, we focused on transforming growth factor-ß-activated kinase 1 (TAK1) mitogen-activated protein kinase (MAPK) kinase kinase, a key regulator of the TNF--induced activation of p65/RelA and c-Jun NH₂-terminal kinase/p38 MAPKs. In human cervical carcinoma HeLa cells, TRAIL induced the delayed phosphorylation of endogenous TAK1 and its activator protein TAB1 and TAB2, which contrasted to the rapid response to TNF-. Specific knockdown of TAK1 using small interfering RNA (siRNA) abrogated the TRAIL-induced activation of p65 and c-Jun NH₂-terminal kinase/p38 MAPKs. TRAIL-induced apoptotic signals, including caspase-8, caspase-3, caspase-7, and poly(ADP-ribose) polymerase, were enhanced by TAK1 siRNA. Flow cytometry showed that the binding of Annexin V to cell surface was also synergistically increased by TRAIL in combination with TAK1 siRNA. In addition, pretreatment of cells with 5Z-7-oxozeaenol, a selective TAK1 kinase inhibitor, enhanced the TRAIL-induced cleavage of caspases and binding of Annexin V. The TAK1-mediated antiapoptotic effects were also observed in human lung adenocarcinoma A549 cells. In contrast, TAK1-deficient mouse embryonic fibroblasts are resistant to TRAIL-induced apoptosis, and treatment of control mouse embryonic fibroblasts with 5Z-7-oxozeaenol did not drastically promote the TRAIL-induced activation of a caspase cascade. These results suggest that TAK1 plays a critical role for TRAIL-induced apoptosis, and the blockade of TAK1 kinase will improve the chances of overcoming cancer. [Mol Cancer Ther 2006;5(12):2970–6]

Grant support: Grant-in-Aids for Scientific Research (C) no. 17590055 and 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/28/06; revised 9/13/06; accepted 10/18/06.