PI3K_Akt_mTOR信号通路与自噬及肿瘤的关系_舒婷

ISSN1007-7626CN11-3870/Qhttp//cjbmb．bjmu．edu．cnChineseJournalofBiochemistryandMolecularBiology20161132111192～1196··DOI10.13865/j．cnki．cjbmb．2016.11.03PI3K/Akt/mTOＲ*330006“”、、。“”。PI3K/Akt/mTOＲPI3PI3K、BPKB/AktmTOＲ3。PI3K/Akt/mTOＲ。PI3K/Akt/mTOＲQ591.1PI3K/Akt/mTOＲSignalingPathwayandItsＲoleinAutophagyandTumorSHUTingWANFu-Sheng*DepartmentofBiochemistryandMolecularBiologyBasicMedicalCollegeofNanchangUniversityNanchang330006ChinaAbstractAutophagyisaself-digestingmechanismthatcharacteristicsofoccurringdouble-membranevesiclesparceledlong-livedproteinsanddamagedorganellesandplaysanessentialroleinmaintainingcellhomeostasisdevelopmenttumorigenesisandinfection．Ｒecentlymanystudieshaveshownthatautophagyactsasadouble-edgedsword．Duringtumordevelopmentandincancertherapyautophagyhasparadoxicallybeenreportedtoplayrolesinpromotingbothcellsurvivalandcelldeath．PI3K/Akt/mTOＲpathwayisacentralregulatingmechanismwhichismadeofphosphoinositide3-kinasePI3KproteinkinaseBAktandmammaliantargetofrapamycinmTOＲcontributingtotumorgrowthandsurvivalandinhibitingautophagy．ThisarticlegivesanoverviewofPI3K/Akt/mTOＲpathwayanditslinkstoautophagyandtumor．KeywordsautophagyPI3K/Akt/mTOＲsignalingpathwaytumor2016-08-272016-09-242016-09-26No．81360032*[e-mail]272016ＲevisedSeptember242016AcceptedSeptember262016SupportedbyNationalNaturalScienceFoundationofChinaNo．81360032*[e-mail]ⅡtypeⅡprogrammedcelldeath“”。。5123451。23-/B/phosphatidylinositol-3-kinase/proteinkinaseB/themammaliantargetofrapamycinPI3K/Akt/mTOＲ。PI3K/Akt/mTOＲ、。1PI3K/Akt/mTOＲPI3K/Akt/mTOＲPI3PI3K、11PI3K/Akt/mTOＲBPKB/AktmTOＲ3Fig．1、、。PI3K3'-OHⅠ、Ⅱ、ⅢⅠPI3KPI3KCⅠ、、ⅡPI3KPI3KCⅡⅢPI3KPI3KCⅢVps34。PI3K/Akt/mTOＲPI3KⅠPI3KⅠPI3K/AktmTOＲ3。ⅢPI3KVps34Beclin1Vps15PI3KCⅢ4mTOＲ。Fig．1PI3K/Akt/mTOＲsignalingpathwayinautophagyPI3KactivationmayoccurviaＲASmutationandbylossofPTEN．ActivationofthePI3K/AKT/mTOＲpathwaycandecreaseULK1andinhibitautophagyAktPI3K/Akt/mTOＲ。AktTSC1/2、mTOＲ。ⅠPI3K45-PI45-P2PIP3453/AKTPDK1Akt-308。mTOＲmTOＲmTOＲC1mTOＲC2。mTOＲC1、。mTOＲC1ULK1ULKmTOＲC1ULK15。KrestyC-PACPI3K/Akt/mTOＲOE196。ZhouPI3K/Akt/mTOＲ7。2PI3K/Akt/mTOＲ、PI3K/Akt/mTOＲPI3K/Akt/mTOＲ。2.1、PI3K/Akt/mTOＲ、、。mTOＲ。mTOＲ。、mTOＲ。AktTSC1/2ＲasＲhebGTPmTOＲ。PI3K/AktmTOＲmTOＲC1ULK1/2ATG1、mATG13、FIP200Atg101mTOＲmTOＲmTOＲULK1ATG13ULK1。LBK/AMPKmTOＲC1ULKmTOＲULK1ATG13FIP2008。AMPAMPKULK1391132ULK1。KimAMPKmTOＲC1ULK1757ULK1-AMPK9。ULK1TＲIM5αBeclin-1Beclin-1。Beclin-1ⅢPI3K/Vps3410。Atg1-Atg13Atg1。mTOＲC1Atg1Atg13mTOＲC1Atg13Atg1。Atg13mTOＲC1Atg1Atg1-Atg1311。2.2PI3K/Akt/mTOＲPI3K/Akt/mTOＲMYCＲASPTENp53。2.2.1PI3K/Akt/mTOＲmTOＲC1MYCPI3K12。mTOＲC2FOXOmiＲNAMYC13。BalakumaranMYCMYCmTOＲMYC4EBP1MYC4EBP15'14。4EBP1MYC。ＲASＲASPI3K/Akt/mTOＲ。ＲASＲAS。SchmuklerNIH3T3K-ＲASG12VPI3K/Akt/mTOＲ15。MorganK-ＲASPIK3CALC316。ＲASPI3K/Akt/mTOＲＲAS17。2.2.2PI3K/Akt/mTOＲPTEN、p53PI3K/Akt/mTOＲ。PTEN10。PTENPI3KPI3K/Akt/mTOＲ、。PTENPI3K/Akt/mTOＲ、。DeAmicisPTENPI3K/AktUVＲAG18。PTENAkt、。HouPTENPI3K-Akt19。MorganPTENPI3K/Akt/mTOＲ30%～50%PI3K/Akt/mTOＲ20。p53。p53AMPKβ1、β2γAMPKmTOＲC121。ChoudhuryULK1、BECN1ATG5p53BECN1ATG5p5322。p53p53。DNAp5323。p53mTOＲ。p53。p53FIP200FAK491111PI3K/Akt/mTOＲAtg17ULK1-FIP200-ATG13-ATG10124。p53mTOＲ。p53p53AMPKTSC1/TSC2mTOＲ。ＲB、LBK1mTOＲ。3。。。3.125。mTOＲ、AktBcl-226。Beclin-1、UVＲAGBif-1、27。、28。。29。PI3K/Akt/mTOＲ30。Goussetis、31。3.232。、33。34。LockＲas、、35。36。37。Ｒuan38。YangPI3K/mTOＲ39。p53、DNA。40。。ＲAD001mTOＲ。ＲAD00141。。。42。4。。、。、。PI3K/AKT/mTOＲ591132。Ｒeferences1YangZKlionskyDJ．EatenaliveahistoryofmacroautophagyJ．NatCellBiol2010129814-8222Prieto-DominguezNOrdonezＲFernandezAetal．ModulationofautophagybysorafenibeffectsontreatmentresponseJ．FrontPharmacol201671513ＲodonJDienstmannＲSerraVetal．DevelopmentofPI3KinhibitorslessonslearnedfromearlyclinicaltrialsJ．NatＲevClinOncol2013103143-1534ItakuraEMizushimaN．CharacterizationofautophagosomeformationsitebyahierarchicalanalysisofmammalianAtgproteinsJ．Autophagy201066764-7765ＲussellＲCYuanHXGuanKL．AutophagyregulationbynutrientsignalingJ．CellＲes201424142-576KrestyLAWehKMZeyzus-JohnsBetal．CranberryproanthocyanidinsinhibitesophagealadenocarcinomainvitroandinvivothroughpleiotropiccelldeathinductionandPI3K/AKT/mTOＲinactivationJ．Oncotarget201563233438-334557ZhouZWLiXXHeZXetal．Inductionofapoptosisandautophagyviasirtuin1-andPI3K/Akt/mTOＲ-mediatedpathwaysbyplumbagininhumanprostatecancercellsJ．DrugDesDevelTher201591511-15548SunSY．Enhancingperifosine’santicancerefficacybypreventingautophagyJ．Autophagy201061184-1859KimJKunduMViolletBetal．AMPKandmTOＲregulateautophagythroughdirectphosphorylationofUlk1J．NatCellBiol2011132132-14110MandellMAJainAArko-MensahJetal．TＲIMproteinsregulateautophagyandcantargetautophagicsubstratesbydirectrecognitionJ．DevCell2014304394-40911KamadaYYoshinoKKondoCetal．mTOＲdirectlycontrolstheAtg1kinasecomplextoregulateautophagyJ．MolCellBiol20103041049-105812LeoneＲDAmaravadiＲK．AutophagyatargetablelinchpinofcancercellmetabolismJ．TrendsEndocrinolMetab2013244209-21713MasuiKTanakaKAkhavanDetal．mTOＲcomplex2controlsglycolyticmetabolisminglioblastomathroughFoxOacetylationandupregulationofc-MycJ．CellMetab2013185726-73914