RESUMEN
Nonsense mutations cause about 10% of genetic disease cases, and no treatments are available. Nonsense mutations can be corrected by molecules with nonsense mutation readthrough activity. An extract of the mushroom Lepista inversa has recently shown high-efficiency correction of UGA and UAA nonsense mutations. One active constituent of this extract is 2,6-diaminopurine (DAP). In Calu-6 cancer cells, in which TP53 gene has a UGA nonsense mutation, DAP treatment increases p53 level. It also decreases the growth of tumors arising from Calu-6 cells injected into immunodeficient nude mice. DAP acts by interfering with the activity of a tRNA-specific 2'-O-methyltransferase (FTSJ1) responsible for cytosine 34 modification in tRNATrp. Low-toxicity and high-efficiency UGA nonsense mutation correction make DAP a good candidate for the development of treatments for genetic diseases caused by nonsense mutations.
Asunto(s)
2-Aminopurina/análogos & derivados , 2-Aminopurina/farmacología , Codón sin Sentido/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Mutación/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes p53/genética , Células HEK293 , Células HeLa , Humanos , Lepisma/química , Ratones , Ratones Desnudos , ARN de Transferencia/genética , ARNt Metiltransferasas/metabolismoRESUMEN
The present study examined the role of a polysaccharide (LSP, 25 and 100⯵g/ml) from the fruiting bodies of Lepista sordid on the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO) in HepG2 cells, and the possible mechanism of action. IDO expression and kynurenine production from LSP-treated HepG2 cells following IFN-γ stimulation were dramatically inhibited by LSP treatment. In line with this, the medium of HepG2 cells pretreated with LSP improved the survival rate of primary CD4+ and CD8+ T cells as compared with IFN-γ-treated control cells. Moreover, tyrosine 701 and serine 727 phosphorylation of STAT1 were dramatically reduced by LSP pretreatment in IFN-γ-stimulated HepG2 cells. Furthermore phosphorylation of JAK-1 and JAK-2 was also inhibited by LSP. Additionally, two IDO promoters (GAS and ISRE) were inhibited in cells pretreated with LSP prior to IFN-γ exposure. These findings suggest that LSP exerts antitumor effects on HepG2 cells by inhibiting IDO via JAK-PKC-δ-STAT1 signaling pathway.