Department of General Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
PLoS One. 2013 Oct 25;8(10):e74272. doi: 10.1371/journal.pone.0074272. eCollection 2013.
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.
大多数人类胰腺癌细胞对肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）介导的细胞凋亡具有抗性。然而，胰腺癌细胞利用其细胞外分子来对抗 TNF 家族介导的促凋亡信号的机制在很大程度上尚不清楚。在这项研究中，我们首次证明，高表达于恶性胰腺癌细胞的分泌型诱饵受体 DcR3 可通过与 TRAIL 结合并拮抗其促凋亡功能，作为一种细胞外抗凋亡分子发挥作用。用 siRNA 降低 DcR3 水平可揭示 TRAIL 并极大增强 TRAIL 诱导的细胞凋亡。吉西他滨是一种用于治疗胰腺癌的一线药物，也可降低 DcR3 的水平。添加 DcR3 siRNA 可进一步增强吉西他滨诱导的细胞凋亡。值得注意的是，我们的体内研究表明，通过进一步降低 DcR3 水平可增强吉西他滨的治疗效果，这表明下调肿瘤细胞中的 DcR3 可使胰腺细胞向凋亡倾斜，并可能成为胰腺癌治疗的新策略。
