IPS-1 differentially induces TRAIL, BCL2, BIRC3 and PRKCE in type I interferons-dependent and -independent anticancer activity.
IPS-1 differentially induces TRAIL, BCL2, BIRC3 and PRKCE in type I interferons-dependent and -independent anticancer activity.
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DOI：
10.1038/cddis.2015.122
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发表时间：
2015-05-07
影响因子：
9
通讯作者：
Kumar H
中科院分区：
文献类型：
--
作者：
Kumar S;Ingle H;Mishra S;Mahla RS;Kumar A;Kawai T;Akira S;Takaoka A;Raut AA;Kumar H
rig -I样受体是RNA病毒的关键细胞质传感器，在抗病毒先天免疫中通过唯一的适配器IFN-β启动子刺激因子-1（也称为Cardif， MAVS和VISA）诱导I型干扰素（IFN）和促炎细胞因子的产生。这些传感器还通过诱导细胞凋亡在抗癌活性中发挥关键作用。然而，人们对其抗癌活性的机制知之甚少。本研究表明，抗癌疫苗佐剂PolyIC（主要由MDA5感测）和溶瘤病毒新城疫病毒NDV（由rig - 1感测）可诱导抗癌活性。IPS-1在I型ifn应答和非应答癌细胞中的异位表达可诱导抗癌活性。PolyIC转染和NDV感染上调促凋亡基因TRAIL，下调抗凋亡基因BCL2、BIRC3和PRKCE。此外，在ifn无应答的癌细胞中，IPS-1、IRF3或IRF7的稳定敲低通过TRAIL和抗凋亡基因抑制凋亡，显示出抗癌活性降低。综上所述，我们的研究表明，IPS-1通过I型ifn依赖和不依赖的方式，通过IRF3和IRF7上调促凋亡基因TRAIL，下调抗凋亡基因BCL2、BIRC3和PRKCE，从而诱导肿瘤活性。
RIG-I-like receptors are the key cytosolic sensors for RNA viruses and induce the production of type I interferons (IFN) and pro-inflammatory cytokines through a sole adaptor IFN-β promoter stimulator-1 (IPS-1) (also known as Cardif, MAVS and VISA) in antiviral innate immunity. These sensors also have a pivotal role in anticancer activity through induction of apoptosis. However, the mechanism for their anticancer activity is poorly understood. Here, we show that anticancer vaccine adjuvant, PolyIC (primarily sensed by MDA5) and the oncolytic virus, Newcastle disease virus (NDV) (sensed by RIG-I), induce anticancer activity. The ectopic expression of IPS-1 into type I IFN-responsive and non-responsive cancer cells induces anticancer activity. PolyIC transfection and NDV infection upregulate pro-apoptotic gene TRAIL and downregulate the anti-apoptotic genes BCL2, BIRC3 and PRKCE. Furthermore, stable knockdown of IPS-1, IRF3 or IRF7 in IFN-non-responsive cancer cells show reduced anticancer activity by suppressing apoptosis via TRAIL and anti-apoptotic genes. Collectively, our study shows that IPS-1 induces anticancer activity through upregulation of pro-apoptotic gene TRAIL and downregulation of the anti-apoptotic genes BCL2, BIRC3 and PRKCE via IRF3 and IRF7 in type I IFN-dependent and -independent manners.