title: Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity.
abstract: RNase L and RNA-dependent protein kinase (PKR) are effectors of the interferon antiviral response that share homology in their pseudokinase and protein kinase domains, respectively. Sunitinib is an orally available, ATP-competitive inhibitor of VEGF and PDGF receptors used clinically to suppress angiogenesis and tumor growth. Sunitinib also impacts IRE1, an endoplasmic reticulum protein involved in the unfolded protein response that is closely related to RNase L. Here, we report that sunitinib is a potent inhibitor of both RNase L and PKR with IC(50) values of 1.4 and 0.3 μM, respectively. In addition, flavonol activators of IRE1 inhibited RNase L. Sunitinib treatment of wild type (WT) mouse embryonic fibroblasts resulted in about a 12-fold increase in encephalomyocarditis virus titers. However, sunitinib had no effect on encephalomyocarditis virus growth in cells lacking both PKR and RNase L. Furthermore, oral delivery of sunitinib in WT mice resulted in 10-fold higher viral titers in heart tissues while suppressing by about 2-fold the IFN-β levels. In contrast, sunitinib had no effect on viral titers in mice deficient in both RNase L and PKR. Also, sunitinib reduced mean survival times from 12 to 6 days in virus-infected WT mice while having no effect on survival of mice lacking both RNase L and PKR. Results indicate that sunitinib treatments prevent antiviral innate immune responses mediated by RNase L and PKR.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Babal Kant
authors.initials: BK
authors.lastname: Jha
authors.forename: Irina
authors.initials: I
authors.lastname: Polyakova
authors.forename: Patricia
authors.initials: P
authors.lastname: Kessler
authors.forename: Beihua
authors.initials: B
authors.lastname: Dong
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dickerman
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018188:Cardiovirus Infections / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D004686:Encephalomyocarditis virus; D004722:Endoribonucleases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics; D007211:Indoles / Q000494:pharmacology*; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D008565:Membrane Proteins; D011758:Pyrroles; C403982:ERN2 protein, human; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D000077210:Sunitinib