The prostaglandin E2 receptor, EP2, regulates survivin expression via an EGFR/STAT3 pathway in UVB-exposed mouse skin.
We previously reported that cycloogenase (COX)-2-generated prostaglandin E2 (PGE2) 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 PGE2 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 PGE2 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, PGE1 alcohol, did not significantly increase p-STAT3 or survivin levels. These data suggest that COX-2-generated PGE2 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.
Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Kyung-Soo
KS
Chun
Robert
R
Langenbach
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects; D000077022:Survivin; D014466:Ultraviolet Rays
C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000077022:Survivin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C541485:EGFR protein, mouse; D066246:ErbB Receptors