Oncotarget

Research Papers:

The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-β1-induced growth inhibition by targeting Smad3 linker region

Woo-Kwang Jeon, Jiyeon Choi, Seong Ji Park, Eun Ji Jo, Young K. Lee, Seunghwan Lim, Jae-Hong Kim, John J. Letterio, Fang Liu, Seong-Jin Kim and Byung-Chul Kim _

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Oncotarget. 2015; 6:41650-41666. https://doi.org/10.18632/oncotarget.6146

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Abstract

Woo-Kwang Jeon1,*, Jiyeon Choi1,*, Seong Ji Park1, Eun Ji Jo1, Young K. Lee2, Seunghwan Lim3, Jae-Hong Kim4, John J. Letterio3, Fang Liu5, Seong-Jin Kim6 and Byung-Chul Kim1

1 Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea

2 Department of Statistics, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea

3 Department of Pediatrics, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

4 College of Life Sciences and Biotechnology, Korea University, Seoul, Korea

5 Center for Advanced Biotechnology and Medicine, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

6 CHA Cancer Institute and Department of Biomedical Science, College of Life Science, CHA University, Seongnam City, Republic of Korea

* These authors have contributed equally to this work

Correspondence to:

Byung-Chul Kim, email:

Keywords: LTB4, BLT1, Smad3 linker region phosphorylation, TGF-β1 resistance, cancer cell growth

Received: May 19, 2015 Accepted: September 30, 2015 Published: October 19, 2015

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-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.


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