IPS-1 differentially induces TRAIL, BCL2, BIRC3 and PRKCE in type I interferons-dependent and -independent anticancer activity.

S Kumar,A A Raut,A Takaoka,A Kumar,H Ingle,R S Mahla,S Akira,H Kumar,T Kawai,S Mishra

doi:10.1038/cddis.2015.122

Abstract

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.

Highlights

In addition to the pivotal role that host immunity has against numerous pathogen challenges, it is crucial in immune surveillance against altered-self cells
We first tested the expression of TLR3 in HEK293T, MDAMB-231 and IMR32 cells using semi-quantitative PCR and quantitative real-time PCR (Supplementary Figure S1).We found that HEK293T cells expresses low level of TLR3 compared to other tested cell lines
Our results suggest that PolyIC stimulation induce low level of cytotoxic effects compared with PolyI:C-transfection suggesting RIGI-like receptors (RLRs) signaling pathway is having a predominant role in the induction of cytotoxic effect compared with TLR3 signaling pathway

Summary

Introduction

In addition to the pivotal role that host immunity has against numerous pathogen challenges, it is crucial in immune surveillance against altered-self cells Immune mediators such as cytokines, chemokines and type I IFN initiate a complex network of signals to induce an anti-tumor state by triggering various biochemical processes such as cell cycle arrest and apoptosis. The RLR pathway induces anticancer activity through the selective induction of cell death or apoptosis via upregulation of the pro-apoptotic gene TRAIL and downregulation of the anti-apoptotic genes BCL2, BIRC3 and PRKCE. These changes lead to post-translational activation of caspases − 3 and − 9 and PARP-1 in cancer cells. Our study reveals that IFN regulatory factors (IRF)[3] and IRF7 are indispensable for the RLR-mediated anticancer activity

Methods

Results

Conclusion