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IPS-1 differentially induces TRAIL, BCL2, BIRC3 and PRKCE in type I interferons-dependent and -independent anticancer
1Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
Cell Death & Disease
|May 8, 2015
Summary
RIG-I-like receptors and their adaptor IPS-1 activate anticancer immunity. They promote cancer cell death by upregulating pro-apoptotic TRAIL and downregulating anti-apoptotic genes, independent of type I interferons.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- RIG-I-like receptors (RLRs) are crucial cytosolic sensors for RNA viruses, initiating innate immune responses.
- RLRs, via the adaptor IFN-β promoter stimulator-1 (IPS-1), induce type I interferons and pro-inflammatory cytokines.
- RLRs also play a role in anticancer activity through apoptosis induction, but the mechanisms remain unclear.
Purpose of the Study:
- To elucidate the mechanism by which RLRs and IPS-1 mediate anticancer activity.
- To investigate the role of IPS-1 in regulating apoptotic genes in cancer cells.
- To determine if IPS-1's anticancer effects are dependent on type I interferons.
Main Methods:
- Utilized PolyIC (MDA5 ligand) and Newcastle disease virus (NDV, RIG-I ligand) to stimulate RLRs in cancer cells.
- Ectopically expressed IPS-1 in type I IFN-responsive and non-responsive cancer cells.
- Performed gene expression analysis to assess pro- and anti-apoptotic gene regulation.
- Used stable knockdown of IPS-1, IRF3, and IRF7 in cancer cells to evaluate their roles.
Main Results:
- PolyIC and NDV induced anticancer activity, which was also mediated by ectopic IPS-1 expression.
- IPS-1 expression modulated apoptotic gene profiles, upregulating pro-apoptotic TRAIL and downregulating anti-apoptotic BCL2, BIRC3, and PRKCE.
- Knockdown of IPS-1, IRF3, or IRF7 impaired anticancer activity by affecting apoptosis regulation.
Conclusions:
- IPS-1 is a key mediator of anticancer activity induced by RLR activation.
- IPS-1 regulates apoptosis through TRAIL and anti-apoptotic genes (BCL2, BIRC3, PRKCE) via IRF3 and IRF7.
- The anticancer effects of IPS-1 operate through both type I IFN-dependent and -independent pathways.
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