Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid.
Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid.
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DOI：
10.1158/0008-5472.can-14-0819
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Emdad L
中科院分区：
文献类型：
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作者：
Bhoopathi P;Quinn BA;Gui Q;Shen XN;Grossman SR;Das SK;Sarkar D;Fisher PB;Emdad L
聚肌苷-聚胞苷酸（Polyinosine-polycytidylic acid，pIC）是一种合成的dsRNA，其作为TLR 3和RLR的免疫激动剂来激活可以杀死肿瘤细胞的树突状细胞和NK细胞。pIC也可以触发胰腺导管腺癌细胞的凋亡，但其作用机制尚不清楚。在这项研究中，我们研究了pIC与聚乙烯亚胺（[pIC]PEI）的制剂在PDAC中的潜在治疗活性，并研究了其作用机制。[pIC]PEI刺激PDAC细胞的凋亡，而不影响正常胰腺上皮细胞。在机制上，[pIC]PEI抑制XIAP和存活素表达，并通过诱导MDA-5、RIG-I和NOXA激活免疫应答。PDAC中的[pIC]PEI抑制AKT的磷酸化，该事件对于通过XIAP和存活素降解刺激细胞凋亡至关重要。在PDAC的皮下和准原位模型中，[pIC]PEI的体内施用通过AKT介导的XIAP降解抑制肿瘤生长。总之，这些结果为评价[pIC]PEI作为治疗胰腺癌的免疫化疗提供了临床前概念验证。
Polyinosine-polycytidylic acid (pIC) is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and NK cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells but its mechanism of action is obscure. In this study, we investigated the potential therapeutic activity of a formulation of pIC with polyethylenimine ([pIC]PEI) in PDAC and investigated its mechanism of action. [pIC]PEI stimulated apoptosis in PDAC cells without affecting normal pancreatic epithelial cells. Mechanistically, [pIC]PEI repressed XIAP and survivin expression and activated an immune response by inducing MDA-5, RIG-I and NOXA. Phosphorylation of AKT was inhibited by [pIC]PEI in PDAC and this event was critical for stimulating apoptosis through XIAP and survivin degradation. In vivo administration of [pIC]PEI inhibited tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic-models of PDAC. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC]PEI as an immunochemotherapy to treat pancreatic cancer.