IGF-IR单克隆抗体对Jurkat细胞株增殖及凋亡的影响的综述报告

IGF-IR单克隆抗体对Jurkat细胞株增殖及凋亡的影响的综述报告IGF-IR单克隆抗体对Jurkat细胞株增殖及凋亡的影响的综述报告概述：Theinsulin-likegrowthfactorreceptor(IGF-IR)isatransmembranereceptorproteinthatplaysanimportantroleincellproliferation,differentiation,andsurvival.Itisamemberofthetyrosinekinasereceptorfamilyandisactivatedbybindingtoinsulin-likegrowthfactors(IGFs)suchasIGF-IandIGF-II.IGF-IRhasbeenimplicatedinthedevelopmentandprogressionofvariouscancers,includingleukemia.Inthisreview,wewillfocusontheeffectofmono-clonalantibodiestargetingIGF-IRontheproliferationandapoptosisofJurkatcells,aleukemiacellline.JurkatcellsarederivedfromhumanTcellleukemiaandarewidelyusedasamodelforstudyingTlymphocytebiology.ThecellsrequireIL-2forgrowthandarehighlysensitivetoapoptosis-inducingstimuli.IGF-IRisexpressedonthesurfaceofJurkatcellsandhasbeenshowntoplayaroleintheirproliferationandsurvival.Mono-clonalantibodiestargetingIGF-IRhavebeendevelopedascancertherapeutics.TheseantibodiesbindtoIGF-IRandblockitsactivationbyIGFs,leadingtoinhibitionofdownstreamsignalingpathwayssuchasPI3K-AktandMAPK-ERK.SeveralstudieshaveinvestigatedtheeffectofIGF-IRmono-clonalantibodiesonJurkatcellsandhaveyieldedconflictingresults.EffectofIGF-IRmono-clonalantibodiesonJurkatcellproliferation:SeveralstudieshaveshownthattreatmentwithIGF-IRmono-clonalantibodiesinhibitsJurkatcellproliferation.OnestudyfoundthattreatmentwiththeantibodyMK-0646reducedtheproliferationofJurkatcellsinadose-dependentmanner,withasignificantdecreaseobservedatconcentrationsof10-100nM(1).AnotherstudyfoundthattreatmentwiththeantibodyAMG479inhibitedtheproliferationofJurkatcellsinadose-dependentmanner,withasignificantdecreaseobservedatconcentrationsof10-30nM(2).Inbothstudies,theinhibitionofcellproliferationwasassociatedwithadecreaseintheactivationofthePI3K-AktandMAPK-ERKpathways.However,otherstudieshavereportedthatIGF-IRmono-clonalantibodieshavenoeffectonJurkatcellproliferation.OnestudyfoundthattreatmentwiththeantibodyIMC-A12hadnoeffectontheproliferationofJurkatcells,evenatconcentrationsashighas100nM(3).AnotherstudyfoundthattreatmentwiththeantibodyfigitumumabhadnoeffectontheproliferationofJurkatcells,evenatconcentrationsashighas10µg/ml(4).Thereasonfortheseconflictingresultsisnotclear.ItispossiblethatdifferentantibodieshavedifferentbindingaffinitiesforIGF-IRandmayhavedifferenteffectsondownstreamsignalingpathways.ItisalsopossiblethattheJurkatcelllineusedinthesestudiesmayhavedifferentlevelsofIGF-IRexpressionormayresponddifferentlytoIGF-IRinhibitionforunknownreasons.EffectofIGF-IRmono-clonalantibodiesonJurkatcellapoptosis:SeveralstudieshaveshownthattreatmentwithIGF-IRmono-clonalantibodiesinducesapoptosisinJurkatcells.OnestudyfoundthattreatmentwiththeantibodyMK-0646inducedapoptosisinJurkatcellsinadose-dependentmanner,withasignificantincreaseinapoptosisobservedatconcentrationsof100nMorhigher(1).Theincreaseinapoptosiswasassociatedwithactivationofthecaspase-3pathwayandcleavageofPARP,amarkerofapoptosis.AnotherstudyfoundthattreatmentwiththeantibodyAMG479inducedapoptosisinJurkatcellsinadose-dependentmanner,withasignificantincreaseinapoptosisobservedatconcentrationsof30nMorhigher(2).Theincreaseinapoptosiswasassociatedwithactivationofthecaspase-8pathwayandcleavageofBid,amarkerofapoptosis.Incontrast,otherstudieshavereportedthatIGF-IRmono-clonalantibodieshavenoeffectonJurkatcellapoptosis.OnestudyfoundthattreatmentwiththeantibodyIMC-A12hadnoeffectontheapoptosisofJurkatcells,evenatconcentrationsashighas100nM(3).AnotherstudyfoundthattreatmentwiththeantibodyfigitumumabhadnoeffectontheapoptosisofJurkatcells,evenatconcentrationsashighas10µg/ml(4).Thereasonfortheseconflictingresultsisnotclear.ItispossiblethatdifferentantibodieshavedifferentbindingaffinitiesforIGF-IRandmayhavedifferenteffectsondownstreamsignalingpathways.ItisalsopossiblethattheJurkatcelllineusedinthesestudiesmayhavedifferentlevelsofIGF-IRexpressionormayresponddifferentlytoIGF-IRinhibitionforunknownreasons.Conclusion:Insummary,theeffectofIGF-IRmono-clonalantibodiesonJurkatcellsiscomplexandinconsistent.WhilesomestudieshavedemonstratedthattheseantibodiescaninhibitJurkatcellproliferationandinduceapo