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Silymarin suppresses the PGE 2 ‐induced cell migration through inhibition of EP2 activation; G protein‐dependent PKA‐CREB and G protein‐independent Src‐STAT3 signal pathways
Author(s) -
Woo Seon Min,
Min KyoungJin,
Chae In Gyeong,
Chun KyungSoo,
Kwon Taeg Kyu
Publication year - 2015
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22092
Subject(s) - prostaglandin e2 receptor , creb , signal transduction , phosphorylation , biology , cell migration , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , stat3 , prostaglandin e , receptor , biochemistry , cell , agonist , transcription factor , gene
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) E 2 ‐induced renal cell carcinoma (RCC) migration and what are the underlying mechanisms are not well elucidated. Here, we found that silymarin markedly inhibited PGE 2 ‐stimulated migration. PGE 2 induced G protein‐dependent CREB phosphorylation via protein kinase A (PKA) signaling, and PKA inhibitor (H89) inhibited PGE 2 ‐mediated migration. Silymarin reduced PGE 2 ‐induced CREB phosphorylation and CRE‐promoter activity. PGE 2 also activated G protien‐independent signaling pathways (Src and STAT3) and silymarin reduced PGE 2 ‐induced phosphorylation of Src and STAT3. Inhibitor of Src (Saracatinib) markedly reduced PGE 2 ‐mediated migration. We found that EP2, a PGE 2 receptor, is involved in PGE 2 ‐mediated cell migration. Down regulation of EP2 by EP2 siRNA and EP2 antagonist (AH6809) reduced PGE 2 ‐inudced migration. In contrast, EP2 agonist (Butaprost) increased cell migration and silymarin effectively reduced butaprost‐mediated cell migration. Moreover, PGE 2 increased EP2 expression through activation of positive feedback mechanism, and PGE 2 ‐induced EP2 expression, as well as basal EP2 levels, were reduced in silymarin‐treated cells. Taken together, our study demonstrates that silymarin inhibited PGE 2 ‐induced cell migration through inhibition of EP2 signaling pathways (G protein dependent PKA‐CREB and G protein‐independent Src‐STAT3). © 2013 Wiley Periodicals, Inc.