Autophagy Induced by HIF1α Overexpression Supports Trophoblast Invasion by Supplying Cellular Energy.docVIP

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Autophagy Induced by HIF1α Overexpression Supports Trophoblast Invasion by Supplying Cellular Energy.doc

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Autophagy Induced by HIF1α Overexpression Supports Trophoblast Invasion by Supplying Cellular Energy

AutophagyInducedbyHIF1aOverexpressionSupports TrophoblastInvasionbySupplyingCellularEnergy MikikoYamanaka-Tatematsu1.,AkitoshiNakashima1.,NaonobuFujita2,TomokoShima1, TamotsuYoshimori2,ShigeruSaito1* 1DepartmentofObstetricsandGynecology,FacultyofMedicine,UniversityofToyama,Toyama,Japan,2DepartmentofGenetics,OsakaUniversityGraduateSchoolof Medicine,Suita,Osaka,Japan Abstract Extravilloustrophoblasts(EVTs)characterizetheinvasionofthematernaldeciduaunderlowoxygenandpoornutritionat theearlyfeto-maternalinterfacetoestablishasuccessfulpregnancy.WepreviouslyreportedthatautophagyinEVTswas activatedunder2%O2invitro,andautophagyactivationwasalsoobservedinEVTsattheearlyfeto-maternalinterfacein vivo.Here,weshowthatautophagyisanenergysourcefortheinvasionofEVTs.Cobaltchloride(CoCl2),whichinduces hypoxiainduciblefactor1a(HIF1a)overexpression,activatedautophagyinHTR8/SVneocells,anEVTcellline.Thenumber ofinvadingHTR8-ATG4BC74Acells,anautophagy-deficientEVTcellline,wasmarkedlyreducedby81percentwiththeCoCl2 treatmentthroughthesuppressionofMMP9level,althoughCoCl2didnotaffectthecellularinvasionofHTR8-mStrawberry cells,acontrolcellline.HTR8-ATG4BC74AcellstreatedwithCoCl2showedadecreaseincellularadenosinetriphosphate(ATP) levelsandacompensatoryincreaseintheexpressionofpurinergicreceptorP2Xligand-gatedionchannel7(P2RX7),which isstimulatedwithATP,whereasHTR8-mStrawberrycellsmaintainedcellularATPlevelsanddidnotaffectP2RX7expression. Furthermore, the decreased invasiveness of HTR8-ATG4BC74A cells treated with CoCl2 was neutralized by ATP supplementationtothelevelofHTR8-ATG4BC74A cellstreatedwithoutCoCl2.Theseresultssuggestthatautophagyplays aroleinmaintaininghomeostasisbycountervailingHIF1a-mediatedcellularenergyconsumptioninEVTs. Citation:Yamanaka-TatematsuM,NakashimaA,FujitaN,ShimaT,YoshimoriT,etal.(2013)AutophagyInducedbyHIF1aOverexpressionSupportsTrophoblast InvasionbySupplyingCellularEnergy.PLoSONE8(10):e76605.doi:10.1371/journal.pone.0076605 Editor:AnaMora,UniversityofPittsburgh,