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《Apoptosis-LikeDeathinBacteriaInducedbyHAMLET,aHumanMilkLipid-ProteinComplex》PLoSONE2011,6(3):1-12美国纽约州立大学；纽约州生物信息学与生命科学卓越中心；瑞典兰德大学；新加坡A*STARApoptosisinducedbyahumanmilkprotein人乳蛋白诱导细胞凋亡Proc.Natl.Acad.Sci.USAVol.92,pp.8064-8068,August1995ABSTRACTTothebreast-fedinfant,humanmilkismorethanasourceofnutrients;itfurnishesawidearrayofmoleculesthatrestrictmicrobes,suchasantibodies,bactericidins,andinhibitorsofbacterialadherence.However,ithasrarelybeenconsideredthathumanmilkmayalsocontainsubstancesbioactivetowardhostcells.Whileinvestigatingtheeffectofhumanmilkonbacterialadherencetoahumanlungcancercellline,weweresurprisedtodiscoverthatthemilkkilledthecells.Analysisofthiseffectrevealedthatacomponentofmilkinaparticularphysicalstate-multimerica-lactalbumin-isapotentCa2+-elevatingandapoptosis-inducingagentwithbroad,yetselective,cytotoxicactivity.Multimerica-lactalbuminkilledalltransformed,embryonic,andlymnphoidcellstestedbutsparedmatureepithelialelements.Thesefindingsraisethepossibilitythatmilkcontributestomucosalimmunitynotonlybyfurnishingantimicrobialmoleculesbutalsobypolicingthefunctionoflymphocytesandepithelium.Finally,analysisofthemechanismbywhichmultimerica-lactalbumininducesapoptosisintransformedepithelialcellscouldleadtothedesignofantitumoragents.对母乳喂养婴儿来说，母乳不仅是营养来源，而且也提供着丰富的分子用以抵御微生物体，如抗体和细菌素，并限制细菌粘附。然而，人们很少想到母乳中也会含有针对宿主细胞的生物活性物质。在调查母乳对细菌粘附到人肺癌细胞株的影响时，我们惊奇地发现母乳杀死了癌细胞。对此结果做进一步分析后得出是母乳中的一种成分，以α-乳白蛋白多聚体形式存在，能够提高钙离子浓度，作为细胞凋亡的诱导剂；并有选择性地发挥对细胞的毒性。α-乳白蛋白多聚体能杀灭所有转化、胚胎和淋巴样细胞，但对成熟的上皮细胞无作用。这些发现提醒我们：母乳有助于粘膜免疫系统不仅是因为产生了抗菌分子，而且也在于policingthefunctionoflymphocytesandepithelium。最后，分析α-乳白蛋白多聚体能在分化的上皮细胞中诱导肿瘤细胞凋亡的机理能为我们设计抗肿瘤药提供思路。HAMLETKillsTumorCellsbyApoptosis:Structure,CellularMechanisms,andTherapyHAMLET通过诱发凋亡杀灭肿瘤细胞：结构，细胞机制和疗效J.Nutr.135:1299–1303,2005.ABSTRACT:Newcancertreatmentsshouldaimtodestroytumorcellswithoutdisturbingnormaltissue.HAMLET(humanα-lactalbuminmadelethaltotumorcells)offersanewmolecularapproachtosolvingthisproblem,becauseitinducesapoptosisintumorcellsbutleavesnormaldifferentiatedcellsunaffected.Afterpartialunfoldingandbindingtooleicacid,α-lactalbuminformstheHAMLETcomplex,whichenterstumorcellsandfreezestheirmetabolicmachinery.ThecellsproceedtofragmenttheirDNA,andtheydisintegratewithapoptosis-likecharacteristics.HAMLETkillsawiderangeofmalignantcellsinvitroandmaintainsthisactivityinvivoinpatientswithskinpapillomas.Inaddition,HAMLEThasstrikingeffectsonhumanglioblastomasinaratxenograftmodel.Afterconvection-enhanceddelivery,HAMLETdiffusesthroughoutthebrain,selectivelykillingtumorcellsandcontrollingtumorprogressionwithoutapparenttissuetoxicity.HAMLETthusshowsgreatpromiseasanewtherapeuticwiththeadvantageofselectivityfortumorcellsandlackoftoxicity.癌症的新疗法应该着眼于摧毁肿瘤细胞但不干扰正常机体组织。HAMLET（能致肿瘤细胞死亡的人α-乳白蛋白）为解决此问题提供了一种新的分子途径，因为它诱导肿瘤细胞凋亡但却不影响正常分化细胞。α-乳白蛋白分子部分展开与油酸结合后形成了HAMLET复合物，进入到肿瘤细胞内部...