RESUMO
Aging and age-related diseases can be viewed as the result of the lifelong accumulation of stress insults. The identification of mutant strains and genes that are responsive to stress and can alter longevity profiles provides new therapeutic targets for age-related diseases. Here we reported that a Drosophila strain with reduced expression of ribose-5-phosphate isomerase (rpi), EP2456, exhibits increased resistance to oxidative stress and enhanced lifespan. In addition, the strain also displays higher levels of NADPH. The knockdown of rpi in neurons by double-stranded RNA interference recapitulated the lifespan extension and oxidative stress resistance in Drosophila. This manipulation was also found to ameliorate the effects of genetic manipulations aimed at creating a model for studying Huntington's disease by overexpression of polyglutamine in the eye, suggesting that modulating rpi levels could serve as a treatment for normal aging as well as for polyglutamine neurotoxicity.
Assuntos
Envelhecimento/metabolismo , Aldose-Cetose Isomerases/genética , Proteínas de Drosophila/genética , Via de Pentose Fosfato/genética , Peptídeos/metabolismo , Envelhecimento/genética , Aldose-Cetose Isomerases/deficiência , Animais , Modelos Animais de Doenças , Proteínas de Drosophila/deficiência , Drosophila melanogaster , Técnicas de Silenciamento de Genes , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Longevidade , Masculino , NADP/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo , Peptídeos/genética , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Markers that could accurately predict responses to the general kinase inhibitor sorafenib are needed to better leverage its clinical applications. In this study, we examined a hypothesized role in the drug response for the growth arrest DNA damage-inducible gene 45ß (GADD45ß), which is commonly underexpressed in hepatocellular carcinoma (HCC) where sorafenib may offer an important new therapeutic option. The anticancer activity of sorafenib-induced GADD45ß expression was tested in a panel of HCC cell lines and xenograft models. We found that GADD45ß mRNA and protein expression were induced relatively more prominently in HCC cells that were biologically sensitive to sorafenib treatment. GADD45ß induction was not found after treatment with either the mitogen-activated protein kinase-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 or the Raf inhibitor ZM336372, suggesting that GADD45ß induction by sorafenib was independent of Raf/MEK/ERK signaling activity. However, c-Jun NH2-terminal kinase (JNK) kinase activation occurred preferentially in sorafenib-sensitive cells. Small interfering RNA-mediated knockdown of GADD45ßor JNK kinase limited the proapoptotic effects of sorafenib in sorafenib-sensitive cells. We defined the -339/-267 region in the GADD45ß promoter containing activator protein-1 and SP1-binding sites as a crucial region for GADD45ß induction by sorafenib. Together, our findings suggest that GADD45ß induction contributes to sorafenib-induced apoptosis in HCC cells, prompting further studies to validate its potential value in predicting sorafenib efficacy.
