Autophagy Protects against Oxaliplatin-Induced Cell Death via ER Stress and ROS in Caco-2 Cells.docVIP

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Autophagy Protects against Oxaliplatin-Induced Cell Death via ER Stress and ROS in Caco-2 Cells.doc

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Autophagy Protects against Oxaliplatin-Induced Cell Death via ER Stress and ROS in Caco-2 Cells

AutophagyProtectsagainstOxaliplatin-InducedCell DeathviaERStressandROSinCaco-2Cells YanShi1.,BinTang2.,Pei-WuYu1*,BoTang1,Ying-XueHao1,XiaoLei1,Hua-XingLuo1 ,Dong- ZhuZeng1* 1Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China, 2DepartmentofClinicalMicrobiologyandImmunology,CollegeofMedicalLaboratoryScience,ThirdMilitaryMedicalUniversity,Chongqing,China Abstract Oxaliplatin is included in a number of effective combination regimens used as first and subsequent lines of therapy for metastaticcolorectalcancer.Accumulatingevidenceindicatesthatautophagyplaysasignificantroleinresponsetocancer therapy.However,theroleofautophagyinoxaliplatin-inducedcelldeathremainstobeclarified.Inthisstudy,weshowed thatoxaliplatininducedcelldeathandautophagyinCaco-2colorectalcancercells.Thesuppressionofautophagyusing eitherpharmacologicinhibitors(3-methyladenine,bafilomycinA1)orRNAinterferenceinessentialautophagygenes(ATG5 orBeclin1)enhancedthecelldeathandreactiveoxygenspecies(ROS)productioninducedbyoxaliplatininCaco-2cells. Blockingoxaliplatin-inducedROSproductionbyusingROSscavengers(NACorTiron)decreasedautophagy.Furthermore, numerousdilatedendoplasmicreticula(ER)werepresentinoxaliplatin-treatedCaco-2cells,andblockingERstressbyRNA interferenceagainstcandidateofmetastasis-1(P8)andC/EBP-homologousprotein(CHOP)decreasedautophagyandROS production.Taken together,these dataindicatethatoxaliplatin activatesautophagy as acytoprotective responsevia ER stressandROSinhumancolorectalcancercells. Citation: Shi Y, Tang B, Yu P-W, Tang B, Hao Y-X, et al. (2012) Autophagy Protects against Oxaliplatin-Induced Cell Death via ER Stress and ROS in Caco-2 Cells.PLoSONE7(11):e51076.doi:10.1371/journal.pone.0051076 Editor:GabrieleMulthoff,TechnischeUniversitaetMuenchen,Germany ReceivedJune19,2012;AcceptedOctober30,2012;PublishedNovember30,2012 Copyright:?2012Shietal.Thisisanopen-accessarticledistributed