Autophagy Inhibitor Chloroquine Enhanced the Cell Death Inducing Effect of the Flavonoid Luteolin in Metastatic Squamous Cell Carcinoma Cells 英文参考文献.docVIP

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Autophagy Inhibitor Chloroquine Enhanced the Cell Death Inducing Effect of the Flavonoid Luteolin in Metastatic Squamous Cell Carcinoma Cells 英文参考文献.doc

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Autophagy Inhibitor Chloroquine Enhanced the Cell Death Inducing Effect of the Flavonoid Luteolin in Metastatic Squamous Cell Carcinoma Cells 英文参考文献

AutophagyInhibitorChloroquineEnhancedtheCell DeathInducingEffectoftheFlavonoidLuteolinin MetastaticSquamousCellCarcinomaCells LienVerschooten1,KathleenBarrette1,SofieVanKelst1,Noem?′RubioRomero2,CharlotteProby3,RitaDe Vos4,PatriziaAgostinis2,MarjanGarmyn1* 1Dermatology,UniversityHospitalsLeuven,DepartmentofOncology,KULeuven,Leuven,Belgium,2CellularandMolecularMedicine,LaboratoryforCellDeathand Therapy,KULeuven,Leuven,Belgium,3CancerResearchUKCancerCentreDundee,CollegeofMedicine,DentistryandNursing,UniversityofDundee,Dundee,Scotland, 4ImagingandPathology,TranslationalCellandTissueResearch,KULeuven,Leuven,Belgium Abstract Background: Flavonoids are widely proposed as very interesting compounds with possible chemopreventive and therapeuticcapacities. Methods Results: In this study, we showed that in vitro treatment with the flavonoid Luteolin induced caspase- dependentcelldeathinamodelofhumancutaneoussquamouscellcarcinoma(SCC)derivedcells,representingamatched pairofprimarytumoranditsmetastasis.Notably,nocytotoxiceffectswereobservedinnormalhumankeratinocyteswhen treated with similar doses of Luteolin. Luteolin-induced apoptosis was accompanied by inhibition of AKT signaling, and sensitivitydecreasedwithtumorprogression,astheprimaryMET1SCCcellswereconsiderablymoresensitivetoLuteolin thantheisogenicmetastaticMET4cells.ExtensiveintracellularvacuolizationwasobservedinLuteolin-treatedMET4cells, whichwerecharacterizedasacidic lysosomalvacuoles,suggestingtheinvolvementofautophagy.Transmissionelectron microscopy,mRFP-GFP-LC3assayandp62proteindegradation,confirmedthatLuteolinstimulatedtheautophagicprocess inthemetastaticMET4cells.BlockingautophagyusingchloroquinemagnifiedLuteolin-inducedapoptosisinthemetastatic SCCcells. Conclusion:Together,theseresultssuggestthatLuteolinhasthecapacitytoinduceselectivelyapoptoticcelldeathbothin primarycutaneousSCCcellsandinmetastaticSCCcellsincombinationwithchloroquine,aninhibitorofautophagosomal degradation.Hence,Luteolinmightbeapromisinga