Targeting of TGF-β-activated protein kinase 1 inhibits chemokine (C-C motif) receptor 7 expression, tumor growth and metastasis in breast cancer
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1Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, Republic of China
2National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China
3Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China
4Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan, Republic of China
5Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, Republic of China
*These authors have contributed equally to this work
Ming-Feng Hou, e-mail: email@example.com
Wen-Chun Hung, e-mail: firstname.lastname@example.org
keywords: TGF-β-activated protein kinase 1 (TAK1), TAK1 binding proteins (TABs), chemokine (C-C motif) receptor 7 (CCR7), NF-κB, c-JUN, lymphatic invasion
Received: August 21, 2014 Accepted: November 11, 2014 Published: December 10, 2014
TGF-β-activated protein kinase 1 (TAK1) is a critical mediator in inflammation, immune response and cancer development. Our previous study demonstrated that activation of TAK1 increases the expression of chemokine (C-C motif) receptor 7 (CCR7) and promotes lymphatic invasion ability of breast cancer cells. However, the expression and association of activated TAK1 and CCR7 in breast tumor tissues is unknown and the therapeutic effect by targeting TAK1 is also unclear. We showed that activated TAK1 (as indicated by phospho-TAK1) and its binding protein TAB1 are strongly expressed in breast tumor tissues (77% and 74% respectively). In addition, increase of phospho-TAK1 or TAB1 is strongly associated with overexpression of CCR7. TAK1 inhibitor 5Z-7-Oxozeaenol (5Z-O) inhibited TAK1 activity, suppressed downstream signaling pathways including p38, IκB kinase (IKK) and c-Jun N-terminal kinase (JNK) and reduced CCR7 expression in metastatic MDA-MB-231 cells. In addition, 5Z-O repressed NF-κB- and c-JUN-mediated transcription of CCR7 gene. Knockdown of TAB1 attenuated CCR7 expression and tumor growth in an orthotopic animal study. More importantly, lymphatic invasion and lung metastasis were suppressed. Collectively, our results demonstrate that constitutive activation of TAK1 is frequently found in human breast cancer and this kinase is a potential therapeutic target for this cancer.
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