A Prokaryotic S1P Lyase Degrades Extracellular S1P In Vitro and In Vivo Implication for Treating Hyperproliferative Disorders 英文参考文献.docVIP

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A Prokaryotic S1P Lyase Degrades Extracellular S1P In Vitro and In Vivo Implication for Treating Hyperproliferative Disorders 英文参考文献.doc

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A Prokaryotic S1P Lyase Degrades Extracellular S1P In Vitro and In Vivo Implication for Treating Hyperproliferative Disorders 英文参考文献

AProkaryoticS1PLyaseDegradesExtracellularS1P InVitroandInVivo:ImplicationforTreating HyperproliferativeDisorders AndreaHuwiler1,FlorenceBourquin2,NataliyaKotelevets1,OleksandrPastukhov1,GuidoCapitani3, MarkusG.Gru¨tter2,UweZangemeister-Wittke1,2* 1Institute of Pharmacology, University of Bern, Bern, Switzerland, 2Institute of Biochemistry, University of Zu¨rich, Zu¨rich, Switzerland, 3Biomolecular Research, Paul ScherrerInstitute,Villigen,Switzerland Abstract Sphingosine-1-phosphate (S1P) regulates a broad spectrum of fundamental cellular processes like proliferation, death, migration and cytokine production. Therefore, elevated levels of S1P may be causal to various pathologic conditions including cancer, fibrosis, inflammation, autoimmune diseases andaberrant angiogenesis. Herewe report that S1Plyase fromtheprokaryoteSymbiobacteriumthermophilum(StSPL)degradesextracellularS1Pinvitroandinblood.Moreover,we investigateditseffectoncellularresponsestypicaloffibrosis,cancerandaberrantangiogenesisusingrenalmesangialcells, endothelialcells,breast(MCF-7)andcolon(HCT116)carcinomacellsasdiseasemodels.Inallcelltypes,wild-typeStSPL,but not an inactive mutant, disrupted MAPK phosphorylation stimulated by exogenous S1P. Functionally, disruption of S1P receptorsignalingbyS1Pdepletioninhibitedproliferationandexpressionofconnectivetissuegrowthfactorinmesangial cells,proliferation,migrationandVEGFexpressionincarcinomacells,andproliferationandmigrationofendothelialcells. UponintravenousinjectionofStSPLinmice,plasmaS1Plevelsrapidlydeclinedby70%within1handthenrecoveredto normal6hafterinjection.Usingthechickenchorioallantoicmembranemodelwefurtherdemonstratethatalsounderin vivoconditionsStSPL,butnottheinactivemutant,inhibitedtumorcell-inducedangiogenesisasanS1P-dependentprocess. OurdatademonstratethatrecombinantStSPLisactiveunderextracellularconditionsandholdspromiseasanewenzyme therapeuticfordiseasesassociatedwithincreasedlevelsofS1PandS1Preceptorsignaling. Citation: Huwiler A, Bourqui