InhibitionofFatty-acidSynthaseInducesCaspase-8-mediated TumorCellApoptosisbyUp-regulatingDDIT4 *□

Fatty-acid synthase (FAS) is up-regulated in a broad rangeof cancers, including those of the breast, prostate, and ova-ries. In tumor cells, the inhibition of FAS elicits cell cyclearrest and apoptosis, so it is considered a potential drug tar-getforoncology.Resultsfromthisstudyshowthatinhibitionof FAS, by either knockdown with small interfering RNA orinhibitionwiththesmallmoleculedrugorlistat,leadstoacti-vation of the receptor-mediated apoptotic cascade (caspase-8-mediated) and ultimately to cell death. However, knockdown oftwo enzymes upstream of FAS, acetyl-CoA carboxylase- andATP-citratelyase,failstoactivatecaspase-8ortoelicitapoptosisintumor cells, even though palmitate synthesis was suppressed.Using differential gene analysis, we traced the unique apoptoticeffectofFASinhibitiontoup-regulationof