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Silymarin suppresses the PGE2-induced cell migration through inhibition of EP2 activation; G protein-dependent PKA-CREB and G protein-independent Src-STAT3 signal pathways

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Author(s)
Seon Min WooKyoung-Jin MinIn Gyeong ChaeKyung-Soo ChunTaeg Kyu Kwon
Keimyung Author(s)
Kwon, Taeg Kyu
Department
Dept. of Immunology (면역학)
Journal Title
Molecular Carcinogenesis
Issued Date
2015
Volume
54
Issue
3
Keyword
silymarinmigrationPGE2EP2renal carcinoma
Abstract
Silymarin has been known as a chemopreventive agent, and possesses multiple anti-cancer activities including induction of apoptosis, inhibition of proliferation and growth, and blockade of migration and invasion. However, whether silymarin could inhibit prostaglandin (PG) E2-induced renal cell carcinoma (RCC) migration and what are the underlying mechanisms are not well elucidated. Here, we found that silymarin markedly inhibited PGE2-stimulated migration. PGE2 induced G protein-dependent CREB phosphorylation via protein kinase A (PKA) signaling, and PKA inhibitor (H89) inhibited PGE2-mediated migration. Silymarin reduced PGE2-induced CREB phosphorylation and CRE-promoter activity. PGE2 also activated G protien-independent signaling pathways (Src and STAT3) and silymarin reduced PGE2-induced phosphorylation of Src and STAT3. Inhibitor of Src (Saracatinib) markedly reduced PGE2-mediated migration. We found that EP2, a PGE2 receptor, is involved in PGE2-mediated cell migration. Down regulation of EP2 by EP2 siRNA and EP2 antagonist (AH6809) reduced PGE2-inudced migration. In contrast, EP2 agonist (Butaprost) increased cell migration and silymarin effectively reduced butaprost-mediated cell migration. Moreover, PGE2 increased EP2 expression through activation of positive feedback mechanism, and PGE2-induced EP2 expression, as well as basal EP2 levels, were reduced in silymarin-treated cells. Taken together, our study demonstrates that silymarin inhibited PGE2-induced cell migration through inhibition of EP2 signaling pathways (G protein dependent PKA-CREB and G protein-independent Src-STAT3).
Keimyung Author(s)(Kor)
권택규
Publisher
School of Medicine
Citation
Seon Min Woo et al. (2015). Silymarin suppresses the PGE2-induced cell migration through inhibition of EP2 activation; G protein-dependent PKA-CREB and G protein-independent Src-STAT3 signal pathways. Molecular Carcinogenesis, 54(3), 216–228. doi: 10.1002/mc.22092
Type
Article
ISSN
1098-2744
Source
https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.22092
DOI
10.1002/mc.22092
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/33451
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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