title: RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation.
abstract: An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, Center for Research Informatics, and The Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, Chicago, IL 60637.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Widau
authors.forename: Akash D
authors.initials: AD
authors.lastname: Parekh
authors.forename: Mark C
authors.initials: MC
authors.lastname: Ranck
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Golden
authors.forename: Kiran A
authors.initials: KA
authors.lastname: Kumar
authors.forename: Ravi F
authors.initials: RF
authors.lastname: Sood
authors.forename: Sean P
authors.initials: SP
authors.lastname: Pitroda
authors.forename: Zhengkai
authors.initials: Z
authors.lastname: Liao
authors.forename: Xiaona
authors.initials: X
authors.lastname: Huang
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Darga
authors.forename: David
authors.initials: D
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Jorge
authors.initials: J
authors.lastname: Andrade
authors.forename: Bernard
authors.initials: B
authors.lastname: Roizman
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Nikolai N
authors.initials: NN
authors.lastname: Khodarev
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000473:pathology; D002470:Cell Survival / Q000502:physiology*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism / Q000502:physiology*; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D020365:RNA Helicases / Q000378:metabolism / Q000502:physiology*; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured
chemical_list: D007370:Interferon Type I; C547666:Dhx58 protein, mouse; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases
keywords: DHX58; cytoplasmic sensor; innate immunity; interferon beta