title: Sigma 1 Receptor plays a prominent role in IL-24-induced cancer-specific apoptosis.
abstract: Interleukin-24 (IL-24), a member of the IL-10 cytokine family, is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. We show that Sigma 1 Receptor (S1R), a ligand-regulated protein chaperone contributes to IL-24 induction of apoptosis. IL-24 generated from an adenovirus expressing IL-24 (Ad.IL-24) induces cancer-specific apoptosis by inducing an endoplasmic reticulum (ER) stress, reactive oxygen species production, and calcium mobilization. The present studies reveals that S1R is required for Ad.IL-24-induced cell death. We provide several lines of evidence to confirm a physical and functional interaction between IL-24 and S1R including: (a) S1R and IL-24 co-localize, as judged by immunocytochemical analysis studies; (b) S1R and IL-24 co-immunoprecipitate using either S1R or IL-24 antibody; (c) S1R agonist (+)-SKF10047 inhibits apoptosis by Ad.IL-24; (d) (+)-SKF10047-mediated inhibition of Ad.IL-24 results in: diminished ER stress protein expression; (e) Calcium mobilization; and (f) ROS production. Collectively, these data demonstrate that S1R interacts with IL-24 and suggest that IL-24:S1R interaction determines apoptosis induction by Ad.IL-24. These studies define Sigma 1 Receptor as a key initial mediator of IL-24 induction of cancer-specific killing. These findings have important implications for our understanding of IL-24 as a tumor suppressor protein as well as an immune modulating cytokine.
authors.affiliation: Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Winchie
authors.initials: W
authors.lastname: Do
authors.forename: Cynthia
authors.initials: C
authors.lastname: Herrera
authors.forename: Jason
authors.initials: J
authors.lastname: Mighty
authors.forename: Maria
authors.initials: M
authors.lastname: Shumskaya
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Redenti
authors.forename: Moira
authors.initials: M
authors.lastname: Sauane
mesh_terms: D017209:Apoptosis; D020013:Calcium Signaling; D053148:Caspase 3 / Q000276:immunology; D045744:Cell Line, Tumor / Q000276:immunology; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007378:Interleukins / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000276:immunology; D017480:Receptors, sigma / Q000819:agonists / Q000276:immunology*; D000097605:Sigma-1 Receptor; D000099180:Interleukin-24
chemical_list: D053148:Caspase 3; D007378:Interleukins; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; D000099180:Interleukin-24
keywords: Apoptosis; ER stress; IL-24; Mechanism; Sigma 1 Receptor; mda-7