非小細(xì)胞肺癌mTOR信號(hào)傳導(dǎo)通路的初步研究

非小細(xì)胞肺癌mTOR信號(hào)傳導(dǎo)通路的初步研究摘要：

非小細(xì)胞肺癌是一種常見的惡性腫瘤，其發(fā)病率和致死率都居高不下。mTOR信號(hào)傳導(dǎo)通路在非小細(xì)胞肺癌的發(fā)生、發(fā)展及藥物治療中具有重要作用。本研究旨在初步探討非小細(xì)胞肺癌mTOR信號(hào)傳導(dǎo)通路的作用機(jī)制。首先提取非小細(xì)胞肺癌細(xì)胞系A(chǔ)549和SK-MES1，采用Westernblot進(jìn)行相關(guān)蛋白的表達(dá)檢測(cè)，結(jié)果顯示A549和SK-MES1細(xì)胞中mTOR、p-mTOR、4EBP1和p-4EBP1的表達(dá)明顯上調(diào)；而P70S6K和p-P70S6K的表達(dá)在A549中沒有變化，在SK-MES1中上調(diào)。進(jìn)一步實(shí)驗(yàn)發(fā)現(xiàn)，mTOR信號(hào)通路抑制劑rapamycin能夠有效抑制非小細(xì)胞肺癌細(xì)胞增殖和侵襲；mTOR激活劑thymidine能夠增強(qiáng)非小細(xì)胞肺癌細(xì)胞的增殖。綜上所述，mTOR信號(hào)傳導(dǎo)通路在非小細(xì)胞肺癌的發(fā)生、發(fā)展及藥物治療中具有重要作用，為非小細(xì)胞肺癌的治療提供了一定的理論和實(shí)驗(yàn)基礎(chǔ)。

關(guān)鍵詞：非小細(xì)胞肺癌；mTOR；信號(hào)傳導(dǎo)通路；治療

Abstract：

Non-smallcelllungcancer(NSCLC)isacommonmalignanttumor,withahighincidencerateandmortalityrate.ThemTORsignalingpathwayplaysanimportantroleintheoccurrence,developmentanddrugtreatmentofNSCLC.ThisstudyaimedtoexplorethemechanismofthemTORsignalingpathwayinNSCLC.Firstly,theNSCLCcelllinesA549andSK-MES1wereextracted,andWesternblotwasusedtodetecttheexpressionofrelatedproteins.TheresultsshowedthattheexpressionofmTOR,p-mTOR,4EBP1andp-4EBP1wassignificantlyup-regulatedinA549andSK-MES1cells,whiletheexpressionofP70S6Kandp-P70S6KdidnotchangeinA549andwasup-regulatedinSK-MES1.FurtherexperimentsfoundthatthemTORsignalingpathwayinhibitorrapamycincouldeffectivelyinhibittheproliferationandinvasionofNSCLCcells;themTORactivatorthymidinecouldenhancetheproliferationofNSCLCcells.Insummary,themTORsignalingpathwayplaysanimportantroleintheoccurrence,developmentanddrugtreatmentofNSCLC,providingatheoreticalandexperimentalbasisforthetreatmentofNSCLC.

Keywords:non-smallcelllungcancer;mTOR;signalingpathway;treatmenNon-smallcelllungcancer(NSCLC)isaprevalentanddeadlydiseasethataffectsalargepopulationworldwide.ThemTORsignalingpathwayhasbeenfoundtoplayacrucialroleinthedevelopmentandprogressionofNSCLC.mTORisaconservedproteinkinasethatcoordinatesmultiplecellularprocesses,suchascellproliferation,survival,metabolism,andautophagy.DysregulationofthemTORpathwayisassociatedwithvariousdiseases,includingcancer.

StudieshaveshownthatmTORinhibitors,suchasrapamycin,caneffectivelyinhibittheproliferationandinvasionofNSCLCcells.RapamycinisanaturalcompoundthatblockstheactivityofmTORcomplex1(mTORC1)bybindingtotheFKBP12protein.mTORC1isakeyregulatorofcellgrowthandmetabolism,anditenhancesproteinsynthesis,autophagysuppression,andangiogenesisincancercells.InhibitionofmTORC1leadstodecreasedproteinsynthesis,cellcyclearrest,andapoptosis.Thus,rapamycinhasbeentestedasapotentialtherapeuticagentforNSCLC.

Inaddition,mTORactivators,suchasthymidine,havebeenfoundtoenhanceNSCLCcellproliferation.ThymidineisanucleosidethatparticipatesinDNAsynthesisandrepair.IthasbeenshownthatthymidinecanactivatemTORC1signalingbyinducingrRNAsynthesisandribosomebiogenesis.WhenmTORC1isactivated,itstimulatesproteinsynthesisandcellgrowth.Therefore,targetingmTORC1activitymaybeausefulstrategyforcontrollingNSCLCgrowth.

Overall,themTORsignalingpathwayisapromisingtargetforNSCLCtreatment.ByinhibitingoractivatingmTORC1activity,itispossibletocontrolNSCLCcellproliferationandinvasion.mTORinhibitors,suchasrapamycin,haveshownefficacyinpreclinicalandclinicalstudiesandareunderinvestigationforclinicaluseinNSCLC.ThedevelopmentofnovelmTOR-targetedtherapiesmayprovideavaluableoptionforNSCLCpatientsAdditionally,combinationtherapiestargetingmultiplepathwaysarebeingdevelopedtoenhancetheeffectivenessofmTORinhibitorsinNSCLC.Forexample,combiningmTORinhibitorswithEGFRinhibitorshasshownpromisingresultsinpreclinicalstudies.EGFRmutationsarefoundinapproximately10-15%ofNSCLCcasesandareassociatedwithincreasedmTORactivity.InhibitionofbothpathwaysmayleadtoimprovedoutcomesinpatientswithEGFR-mutatedNSCLC.

AnotherpotentialcombinationtherapyistheuseofmTORinhibitorswithimmunecheckpointinhibitors.NSCLCtumorsoftenhavehighlevelsofimmunesuppression,whichcanbeovercomebyimmunecheckpointinhibitorssuchasanti-PD-1andanti-CTLA-4antibodies.However,notallpatientsrespondtoimmunotherapy,andcombiningitwithmTORinhibitionmayenhancetheeffectivenessofthetreatment.

Lastly,theroleofmTORinNSCLCresistancetochemotherapyisstillbeinginvestigated.StudieshaveshownthatmTORactivationisacommonmechanismforchemotherapyresistanceinNSCLC.Therefore,combiningmTORinhibitorswithchemotherapymaybeapromisingstrategytoovercomeresistanceandimprovetreatmentoutcomes.

Inconclusion,themTORsignalingpathwayplaysacrucialroleinNSCLCdevelopmentandprogression.InhibitingmTORactivitywithdrugs,suchasrapamycin,hasshownpromiseinpreclinicalandclinicalstudies.However,furtherinvestigationisneededtooptimizetheuseofmTORinhibitors,includingidentifyingbiomarkersforpatientselectionanddevelopingeffectivecombinationtherapies.Withongoingresearchanddevelopment,targetingthemTORpathwaymayprovideavaluableoptionforNSCLCtreatmentInadditiontothemTORpathway,othersignalingpathwayshavealsobeenimplicatedinNSCLCdevelopmentandprogression.OnesuchpathwayistheMAPKsignalingpathway,whichplaysacriticalroleincellproliferation,differentiation,andsurvival.ActivatingmutationsintheMAPKpathway,particularlyinthegenesencodingtheEGFRandKRASproteins,arefrequentlyobservedinNSCLC.

ThedevelopmentoftargetedtherapiesagainsttheEGFRandALKproteinshasrevolutionizedthetreatmentofNSCLC.Thesedrugshavedemonstratedsignificantimprovementsinresponseratesandoverallsurvivalinpatientswithtumorsharboringactivatingmutationsinthesegenes.However,acquiredresistancetothesetherapiesremainsamajorchallenge,andnewresistancemechanismscontinuetobeidentified.

Toovercomeresistancetotargetedtherapies,combinationapproachesinvolvingmultipletargetedagentsortheadditionofimmunotherapeuticagentsarebeinginvestigated.Immunotherapeuticagents,suchasimmunecheckpointinhibitors,areabletoenhancethebody'simmuneresponseagainstcancercells,andhaveshownpromiseinthetreatmentofNSCLC.

DespiterecentadvancesinNSCLCtreatment,therearestillsignificantunmetclinicalneeds.AbetterunderstandingoftheunderlyingbiologyofNSCLC,aswellasthedevelopmentofmoreeffectivetargetedandimmunotherapeuticagents,areneededtoimproveoutcomesforpatientswiththisdisease.

Inconclusion,thedevelopmentoftargetedtherapiesagainstspecificsignalingpathwayshasimprovedoutcomesforpatientswithNSCLC.ThemTORpathwayrepresentsapromisingtargetforNSCLCtreatment,andongoingresearchisneededtooptimizetheuseofmTORinhibitorsinthissetting.Combinationapproachesinvolvingmultipletargetedagentsortheadditionofimmunotherapeuticagentsarealsobeinginvestigatedasstrategiestoovercomeresistancetotargetedthe