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pmid26497676      Oncotarget 2015 ; 6 (39): 41650-66
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  • The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-?1-induced growth inhibition by targeting Smad3 linker region #MMPMID26497676
  • Jeon WK; Choi J; Park SJ; Jo EJ; Lee YK; Lim S; Kim JH; Letterio JJ; Liu F; Kim SJ; Kim BC
  • Oncotarget 2015[Dec]; 6 (39): 41650-66 PMID26497676show ga
  • 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-?1 (TGF-?1) response. We found that LTB4 pretreatment or ectopic expression of BLT1, a high affinity LTB4 receptor, fully abrogated TGF-?1-induced cell cycle arrest and expression of p15INK4B and p27KIP1. Mechanism study revealed that LTB4-mediated suppression of TGF-?1-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-?1-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-?1, providing a novel mechanistic insight into the connection between enhanced inflammatory signal and cancer cell growth.
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