The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-β1-induced growth inhibition by targeting Smad3 linker region.
The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-β1-induced growth inhibition by targeting Smad3 linker region.
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DOI：
10.18632/oncotarget.6146
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发表时间：
2015-12-08
期刊：
影响因子：
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通讯作者：
Kim BC
中科院分区：
文献类型：
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作者：
Jeon WK;Choi J;Park SJ;Jo EJ;Lee YK;Lim S;Kim JH;Letterio JJ;Liu F;Kim SJ;Kim BC
白三烯 B4 (LTB4) 是一种强效促炎类二十烷酸，源自花生四烯酸，已知其信号传导在多种癌症类型中具有促肿瘤作用。在这项研究中，我们研究了增强的 LTB4 信号传导是否会导致对细胞抑制性转化生长因子-β1 (TGF-β1) 反应的抵抗。我们发现 LTB4 预处理或 BLT1（一种高亲和力 LTB4 受体）的异位表达完全消除了 TGF-β1 诱导的细胞周期停滞以及 p15INK4B 和 p27KIP1 的表达。机制研究表明，LTB4介导的对TGF-β1诱导的Smad3激活和生长抑制的抑制是由于通过激活BLT1-NAD(P)H氧化酶(NOX)-活性氧(ROS)-表皮生长因子受体(EGFR)-磷脂酰肌醇3-激酶(PI3-K)-细胞外信号激活增强Smad3连接区(pSmad3L)的磷酸化激酶1/2 (ERK1/2) 连接的信号级联。此外，导致 pSmad3L 的 LTB4/BLT1 信号通路在乳腺癌细胞中被组成型激活，并且与体外和体内细胞的 TGF-β1 抗性生长相关。在人乳腺癌组织中，pSmad3L（Thr179）的表达水平与BLT1表达呈正相关。总的来说，我们的数据首次证明，通过 BLT1-NOX-ROS-EGFR-PI3K-ERK1/2 信号通路诱导 pSmad3L 是 LTB4 阻断 TGF-β1 抗增殖反应的关键机制，为增强炎症信号与癌细胞生长之间的联系提供了新的机制见解。
Leukotriene B4 (LTB4) is a potent pro-inflammatory eicosanoid that is derived from arachidonic acid, and its signaling is known to have a tumor-promoting role in several cancer types. In this study, we investigated whether enhanced LTB4 signaling confers resistance to the cytostatic transforming growth factor-β1 (TGF-β1) response. We found that LTB4 pretreatment or ectopic expression of BLT1, a high affinity LTB4 receptor, fully abrogated TGF-β1-induced cell cycle arrest and expression of p15INK4B and p27KIP1. Mechanism study revealed that LTB4-mediated suppression of TGF-β1-induced Smad3 activation and growth inhibition was due to enhanced phosphorylation of Smad3 linker region (pSmad3L) through activation of BLT1-NAD(P)H oxidase (NOX)-reactive oxygen species (ROS)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3-K)-extracellular signal-activated kinase1/2 (ERK1/2)-linked signaling cascade. Furthermore, the LTB4/BLT1 signaling pathway leading to pSmad3L was constitutively activated in breast cancer cells and was correlated with TGF-β1-resistant growth of the cells in vitro and in vivo. In human breast cancer tissues, the expression level of pSmad3L (Thr179) had a positive correlation with BLT1 expression. Collectively, our data demonstrate for the first time that the induction of pSmad3L through BLT1-NOX-ROS-EGFR-PI3K-ERK1/2 signaling pathway is a key mechanism by which LTB4 blocks the anti-proliferative responses of TGF-β1, providing a novel mechanistic insight into the connection between enhanced inflammatory signal and cancer cell growth.