Lee Dung-Fang, Kuo Hsu-Ping, Chen Chun-Te, Hsu Jung-Mao, Chou Chao-Kai, Wei Yongkun, Sun Hui-Lung, Li Long-Yuan, Ping Bo, Huang Wei-Chien, He Xianghuo, Hung Jen-Yu, Lai Chien-Chen, Ding Qingqing, Su Jen-Liang, Yang Jer-Yen, Sahin Aysegul A, Hortobagyi Gabriel N, Tsai Fuu-Jen, Tsai Chang-Hai, Hung Mien-Chie
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cell. 2007 Aug 10;130(3):440-55. doi: 10.1016/j.cell.2007.05.058.
TNFalpha 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 IKKbeta, a major downstream kinase in the TNFalpha signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKbeta-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKbeta 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.
肿瘤坏死因子α（TNFα）最近已成为一种将炎症与癌症发病机制联系起来的调节因子，但这种联系背后详细的细胞和分子机制仍有待阐明。结节性硬化症1（TSC1）/TSC2肿瘤抑制复合物作为mTOR通路的抑制因子，TSC1/TSC2复合物功能的破坏可能有助于肿瘤发生。在此我们表明，IKKβ是TNFα信号通路中的一种主要下游激酶，它与TSC1在Ser487和Ser511位点发生物理相互作用并使其磷酸化，从而导致TSC1受到抑制。IKKβ介导的TSC1抑制激活了mTOR通路，增强了血管生成，并导致肿瘤发展。我们进一步发现，在多种肿瘤类型中，活化的IKKβ的表达与TSC1的Ser511磷酸化及血管内皮生长因子（VEGF）的产生相关，并且与乳腺癌患者的不良临床预后相关。我们的研究结果确定了一条对于炎症介导的肿瘤血管生成至关重要的通路，并且可能为人类癌症的临床干预提供一个靶点。
