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Most human pancreatic cancer cells are resistant to tumor necrosis factor(TNF)-related apoptosis-inducing ligand(TRAIL)-mediated apoptosis.However,the mechanisms by which pancreatic cancer cells utilize their extracellular molecules to counteract the proapoptotic signaling mediated by the TNF family are largely unknown.In this study,we demonstrate for the first time that DcR3,a secreted decoy receptor that malignant pancreatic cancer cells express at a high level,acts as an extracellular antiapoptotic molecule by binding to TRAIL and counteracting its death-promoting function.The reduction of DcR3 with siRNA unmasked TRAIL and greatly enhanced TRAIL-induced apoptosis.Gemcitabine,a first-line drug for pancreatic cancer,also reduced the level of DcR3.The addition of DcR3 siRNA further enhanced gemcitabine-induced apoptosis.Notably,our in vivo study demonstrated that the therapeutic effect of gemcitabine could be enhanced via further reduction of DcR3,suggesting that downregulation of DcR3 in tumor cells could tip the balance of pancreatic cells towards apoptosis and potentially serve as a new strategy for pancreatic cancer therapy.