Elevated TAK1 augments tumor growth and metastatic capacities of ovarian cancer cells through activation of NF-κB signaling

// Patty C.H. Cai 1 , Lei Shi 2 , Vincent W.S. Liu 1 , Hermit W.M. Tang 1 , Iris J. Liu 1 , Thomas H.Y. Leung 1 , Karen K.L. Chan 1 , Judy W.P. Yam 3 , Kwok-Ming Yao 2 , Hextan Y.S. Ngan 1 and David W. Chan 1 1 Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R.China 2 Department of Biochemistry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R.China 3 Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R.China Correspondence: Hextan YS Ngan, email: // David W Chan, email: // Keywords : TAK1, NF-κB signaling, ovarian cancer, high-grade tumor Received : May 07, 2014 Accepted : July 26, 2014 Published : July 27, 2014 Abstract Transforming growth factor (TGF)-β-activating kinase 1 (TAK1) is a serine/threonine kinase which is frequently associated with human cancer progression. However, its functional role in tumorigenesis is still controversial. Here, we report that TAK1 enhances the oncogenic capacity of ovarian cancer cells through the activation of NF-κB signaling. We found that TAK1 is frequently upregulated and significantly associated with high-grade and metastatic ovarian cancers. Mechanistic studies showed that Ser412 phosphorylation is required for TAK1 in activating NF-κB signaling and promotes aggressiveness of ovarian cancer cells. Conversely, suppression of TAK1 activity by point mutation at Ser412, RNAi mediated gene knockdown or TAK1 specific inhibitor ((5Z) -7-Oxozeaenol) remarkably impairs tumor growth and metastasis in ovarian cancer in vitro and in vivo . Our study underscores the importance of targeting TAK1 as a promising therapeutic approach to counteract the ovarian cancer progression.