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, Byung Chul Kim

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)41650-41666
Number of pages17
JournalOncotarget
Volume6
Issue number39
DOIs
Publication statusPublished - 2015

Fingerprint

Leukotriene B4
Transforming Growth Factors
Growth
Phosphorylation
Epidermal Growth Factor Receptor
Reactive Oxygen Species
Leukotriene B4 Receptors
Phosphatidylinositol 3-Kinase
Breast Neoplasms
Neoplasms
Eicosanoids
NADPH Oxidase
Cytostatic Agents
Cell Cycle Checkpoints
Phosphatidylinositol 3-Kinases
Arachidonic Acid

Keywords

  • BLT1
  • Cancer cell growth
  • LTB
  • Smad3 linker region phosphorylation
  • TGF-β1 resistance

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 6, No. 39, 2015, p. 41650-41666.

Research output: Contribution to journalArticle

Jeon, WK, Choi, J, Park, SJ, Jo, EJ, Lee, YK, Lim, S, Kim, J-H, Letterio, JJ, Liu, F, Kim, SJ & Kim, BC 2015, 'The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-β1-induced growth inhibition by targeting Smad3 linker region', Oncotarget, vol. 6, no. 39, pp. 41650-41666. https://doi.org/10.18632/oncotarget.6146
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. / The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-β1-induced growth inhibition by targeting Smad3 linker region. In: Oncotarget. 2015 ; Vol. 6, No. 39. pp. 41650-41666.
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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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