RESUMEN
Despite progress in identifying molecular drivers of cancer, it has been difficult to translate this knowledge into new therapies, because many of the causal proteins cannot be inhibited by conventional small molecule therapeutics. RNA interference (RNAi), which uses small RNAs to inhibit gene expression, provides a promising alternative to reach traditionally undruggable protein targets by shutting off their expression at the messenger RNA (mRNA) level. Challenges for realizing the potential of RNAi have included identifying the appropriate genes to target and achieving sufficient knockdown in tumors. We have developed high-potency Dicer-substrate short-interfering RNAs (DsiRNAs) targeting ß-catenin and delivered these in vivo using lipid nanoparticles, resulting in significant reduction of ß-catenin expression in liver cancer models. Reduction of ß-catenin strongly reduced tumor burden, alone or in combination with sorafenib and as effectively as DsiRNAs that target mitotic genes such as PLK1 and KIF11. ß-catenin knockdown also strongly reduced the expression of ß-catenin-regulated genes, including MYC, providing a potential mechanism for tumor inhibition. These results validate ß-catenin as a target for liver cancer therapy and demonstrate the promise of RNAi in general and DsiRNAs in particular for reaching traditionally undruggable cancer targets.
Asunto(s)
Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , ARN Interferente Pequeño/genética , beta Catenina/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Masculino , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/química , Interferencia de ARN , ARN Interferente Pequeño/química , ARN Interferente Pequeño/metabolismo , Ribonucleasa III/metabolismo , Carga Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismoRESUMEN
Dopamine-modulated behaviors, including information processing and reward, are subject to behavioral plasticity. Disruption of these behaviors is thought to support drug addictions and psychoses. The plasticity of dopamine-mediated behaviors, for example, habituation and sensitization, are not well understood at the molecular level. We show that in the nematode Caenorhabditis elegans, a D1-like dopamine receptor gene (dop-1) modulates the plasticity of mechanosensory behaviors in which dopamine had not been implicated previously. A mutant of dop-1 displayed faster habituation to nonlocalized mechanical stimulation. This phenotype was rescued by the introduction of a wild-type copy of the gene. The dop-1 gene is expressed in mechanosensory neurons, particularly the ALM and PLM neurons. Selective expression of the dop-1 gene in mechanosensory neurons using the mec-7 promoter rescues the mechanosensory deficit in dop-1 mutant animals. The tyrosine hydroxylase-deficient C. elegans mutant (cat-2) also displays these specific behavioral deficits. These observations provide genetic evidence that dopamine signaling modulates behavioral plasticity in C. elegans.