Dicoumarol sensitizes renal cell carcinoma Caki cells toTRAIL-induced apoptosis through down-regulation of Bcl-2, Mcl-1 and c-FLIP in a NQO1-independent manner

Abstract

In thestudy,weinvestigatedtheeffectofdicoumarol,ananti-coagulantagentwiththeinhibitory activity ofNAD(P)Hquinoneoxidoreductase1(NQO1),onTRAIL-inducedapoptosisinrenal cancer cell.CombinedtreatmentwithdicoumarolandTRAILsignificantly inducedapoptosisin varioushumanrenalcarcinomacellsincludingCaki,ACHN,andA498,butnotinnormalhuman skin fibroblasts (HSF)andmousekidneycells(TMCK-1).Whenweelucidatedtherelevanceof NQO1 indicoumarolplusTRAIL-mediatedapoptosis,bothES936(aNQO1inhibitor)and knockdownofNQO1withsiRNAhadnoeffectonTRAIL-mediatedapoptosis,suggestingthat the stimulatingeffectofdicoumarolonTRAIL-mediatedapoptosisisindependentofNQO1 activity.Wefoundthatdicoumaroltranscriptionallydown-regulatedBcl-2expressionvia inhibition ofNF-κB andCREBactivity,whereasitdown-regulatedMcl-1andc-FLIPexpression at thepost-translationallevel.OverexpressionofBcl-2,Mcl-1,orc-FLIPovercamethedicoumarol plus TRAIL-inducedapoptosis,indicatingthatdown-regualtionoftheseanti-apoptoticproteins may criticallycontributetothesensitizingeffectofdicoumarolonTRAIL-mediatedapoptosis.

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