IKKb Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway

Dung-Fang Lee,1,2 Hsu-Ping Kuo,1,2,10 Chun-Te Chen,1,2,10 Jung-Mao Hsu,1,2,10 Chao-Kai Chou,1,2
Yongkun Wei,1 Hui-Lung Sun,1 Long-Yuan Li,1,3,4 Bo Ping,1,8 Wei-Chien Huang,1 Xianghuo He,1 Jen-Yu Hung,1,9
Chien-Chen Lai,5 Qingqing Ding,1 Jen-Liang Su,1 Jer-Yen Yang,1,2 Aysegul A. Sahin,6 Gabriel N. Hortobagyi,7
Fuu-Jen Tsai,5 Chang-Hai Tsai,4,5 and Mien-Chie Hung1,2,3,4,*
1Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston,
Texas 77030, USA
2The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA
3 Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
4 Asia University, Taichung 413, Taiwan
5China Medical University Hospital, Taichung 404, Taiwan
6Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
7Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
8 Present address: Department of Pathology, Cancer Hospital, Fudan University, Shanghai, P.R. China.
9 Present address: Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
10These authors contributed equally to this work.
*Correspondence: mhung@mdanderson.org
DOI 10.1016/j.cell.2007.05.058

SUMMARY
TNFa has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKb,
a major downstream kinase in the TNFa signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKbmediated TSC1suppression activates themTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKb is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer.