The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-beta 1-induced growth inhibition by targeting Smad3 linker region
DC Field | Value | Language |
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dc.contributor.author | Jeon, Woo-Kwang | - |
dc.contributor.author | Choi, Jiyeon | - |
dc.contributor.author | Park, Seong Ji | - |
dc.contributor.author | Jo, Eun Ji | - |
dc.contributor.author | Lee, Young K. | - |
dc.contributor.author | Lim, Seunghwan | - |
dc.contributor.author | Kim, Jae-Hong | - |
dc.contributor.author | Letterio, John J. | - |
dc.contributor.author | Liu, Fang | - |
dc.contributor.author | Kim, Seong-Jin | - |
dc.contributor.author | Kim, Byung-Chul | - |
dc.date.accessioned | 2021-09-04T09:20:16Z | - |
dc.date.available | 2021-09-04T09:20:16Z | - |
dc.date.created | 2021-06-18 | - |
dc.date.issued | 2015-12-08 | - |
dc.identifier.issn | 1949-2553 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/91596 | - |
dc.description.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. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | IMPACT JOURNALS LLC | - |
dc.subject | CELL-CYCLE ARREST | - |
dc.subject | EPITHELIAL-MESENCHYMAL TRANSITION | - |
dc.subject | LEUKOTRIENE B-4 | - |
dc.subject | FACTOR-BETA | - |
dc.subject | NADPH OXIDASE | - |
dc.subject | TGF-BETA | - |
dc.subject | CHRONIC INFLAMMATION | - |
dc.subject | CANCER CELLS | - |
dc.subject | LUNG-CANCER | - |
dc.subject | KAPPA-B | - |
dc.title | The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-beta 1-induced growth inhibition by targeting Smad3 linker region | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Kim, Jae-Hong | - |
dc.identifier.doi | 10.18632/oncotarget.6146 | - |
dc.identifier.scopusid | 2-s2.0-84951779490 | - |
dc.identifier.wosid | 000366119600019 | - |
dc.identifier.bibliographicCitation | ONCOTARGET, v.6, no.39, pp.41650 - 41666 | - |
dc.relation.isPartOf | ONCOTARGET | - |
dc.citation.title | ONCOTARGET | - |
dc.citation.volume | 6 | - |
dc.citation.number | 39 | - |
dc.citation.startPage | 41650 | - |
dc.citation.endPage | 41666 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Oncology | - |
dc.relation.journalResearchArea | Cell Biology | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.relation.journalWebOfScienceCategory | Cell Biology | - |
dc.subject.keywordPlus | CELL-CYCLE ARREST | - |
dc.subject.keywordPlus | EPITHELIAL-MESENCHYMAL TRANSITION | - |
dc.subject.keywordPlus | LEUKOTRIENE B-4 | - |
dc.subject.keywordPlus | FACTOR-BETA | - |
dc.subject.keywordPlus | NADPH OXIDASE | - |
dc.subject.keywordPlus | TGF-BETA | - |
dc.subject.keywordPlus | CHRONIC INFLAMMATION | - |
dc.subject.keywordPlus | CANCER CELLS | - |
dc.subject.keywordPlus | LUNG-CANCER | - |
dc.subject.keywordPlus | KAPPA-B | - |
dc.subject.keywordAuthor | LTB4 | - |
dc.subject.keywordAuthor | BLT1 | - |
dc.subject.keywordAuthor | Smad3 linker region phosphorylation | - |
dc.subject.keywordAuthor | TGF-beta 1 resistance | - |
dc.subject.keywordAuthor | cancer cell growth | - |
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