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The prostaglandin E 2 receptor, EP2, regulates survivin expression via an EGFR/STAT3 pathway in UVB‐exposed mouse skin
Author(s) -
Chun KyungSoo,
Langenbach Robert
Publication year - 2011
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.20728
Subject(s) - survivin , prostaglandin e2 receptor , stat3 , stat protein , prostaglandin e , biology , apoptosis , cancer research , transcription factor , prostaglandin e2 , receptor , agonist , endocrinology , biochemistry , gene
We previously reported that cycloogenase (COX)‐2‐generated prostaglandin E 2 (PGE 2 ) had anti‐apoptotic effects in UVB‐exposed mouse skin that involved EP2‐mediated signaling (Chun et al., Cancer Res. 2007; 67: 2015). Because survivin is a regulator of cell survival, the possible involvement of COX‐2 and EP2 in survivin expression following UVB exposure of mouse skin was investigated. In wild type mice, UVB exposure time‐dependently increased the levels of survivin and phosphorylated‐signal transducer and activator of transcription 3 (p‐STAT3), a transcription factor that regulates survivin expression; and COX‐2‐ or EP2‐deficiency significantly reduced their induction. Topical application of the COX‐2 inhibitor, celecoxib, also reduced UVB‐induced survivin levels. To further investigate the roles of PGE 2 and EP2 in the regulation of survivin, indomethacin was used to inhibit UVB‐induced endogenous PG production. UVB‐induced survivin levels were reduced by indomethacin, and PGE 2 and the EP2 agonist, butaprost, partially restored survivin levels. The epidermal growth factor receptor (EGFR) is a downstream effector of EP2 and EGFR inhibition (AG1478) significantly reduced UVB activation of STAT3 and survivin levels. UVB‐induced epidermal apoptosis in COX‐2−/− mice was reduced by butaprost and EGFR inhibition blocked butaprost's protective effects. Furthermore, butaprost in the absence of UVB exposure time‐dependently increased p‐EGFR, p‐STAT3, and survivin levels in naïve mouse skin, whereas the EP4 agonist, PGE 1 alcohol, did not significantly increase p‐STAT3 or survivin levels. These data suggest that COX‐2‐generated PGE 2 regulates survivin expression in mouse skin, in part, via an EP2‐mediated EGFR/STAT3 pathway. Therefore, targeting the EP2/survivin pathway may provide a strategy for the chemoprevention/chemotherapy of skin cancer. © 2011 Wiley‐Liss, Inc.