The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-beta 1-induced growth inhibition by targeting Smad3 linker region
- Authors
- Jeon, Woo-Kwang; Choi, Jiyeon; Park, Seong Ji; Jo, Eun Ji; Lee, Young K.; Lim, Seunghwan; Kim, Jae-Hong; Letterio, John J.; Liu, Fang; Kim, Seong-Jin; Kim, Byung-Chul
- Issue Date
- 8-12월-2015
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- LTB4; BLT1; Smad3 linker region phosphorylation; TGF-beta 1 resistance; cancer cell growth
- Citation
- ONCOTARGET, v.6, no.39, pp.41650 - 41666
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOTARGET
- Volume
- 6
- Number
- 39
- Start Page
- 41650
- End Page
- 41666
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/91596
- DOI
- 10.18632/oncotarget.6146
- ISSN
- 1949-2553
- Abstract
- 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-beta 1 (TGF-beta 1) response. We found that LTB4 pretreatment or ectopic expression of BLT1, a high affinity LTB4 receptor, fully abrogated TGF-beta 1-induced cell cycle arrest and expression of p15(INK4B) and p27(KIP1). Mechanism study revealed that LTB4-mediated suppression of TGF-beta 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-beta 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-beta 1, providing a novel mechanistic insight into the connection between enhanced inflammatory signal and cancer cell growth.
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Collections - College of Life Sciences and Biotechnology > Division of Life Sciences > 1. Journal Articles
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