RESUMEN
CUB domain-containing protein-1 (CDCP1) is a trans-membrane protein predominantly expressed in various cancer cells and involved in tumor progression. CDCP1 is phosphorylated at tyrosine residues in the intracellular domain by Src family kinases and recruits PKCδ to the plasma membrane through tyrosine phosphorylation-dependent association with the C2 domain of PKCδ, which in turn induces a survival signal in an anchorage-independent condition. In this study, we used our cell-free screening system to identify a small compound, glycoconjugated palladium complex (Pd-Oqn), which significantly inhibited the interaction between the C2 domain of PKCδ and phosphorylated CDCP1. Immunoprecipitation assays demonstrated that Pd-Oqn hindered the intercellular interaction of phosphorylated CDCP1 with PKCδ and also suppressed the phosphorylation of PKCδ but not that of ERK or AKT. In addition, Pd-Oqn inhibited the colony formation of gastric adenocarcinoma 44As3 cells in soft agar as well as their invasion. In mouse models, Pd-Oqn markedly reduced the peritoneal dissemination of gastric adenocarcinoma cells and the tumor growth of pancreatic cancer orthotopic xenografts. These results suggest that the novel compound Pd-Oqn reduces tumor metastasis and growth by inhibiting the association between CDCP1 and PKCδ, thus potentially representing a promising candidate among therapeutic reagents targeting protein-protein interaction.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Metástasis de la Neoplasia/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Proteína Quinasa C-delta/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Células A549 , Animales , Adhesión Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
One-handed helical oligo(p-benzamide)s were induced via the domino effect based on the planar-axial-helical chirality relay triggered by a planar chiral transition-metal complex at the terminal position as the single chiral source.
Asunto(s)
Benzamidas/química , Dicroismo Circular , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Espectrofotometría , EstereoisomerismoRESUMEN
Cell growth of anaerobic protozoan Tritrichomonas foetus was analyzed. This protozoan usually proliferates in extremely high density, but protozoan parasites were dispersed uniformly in F-bouillon medium and cell division stopped temporarily. However, nuclear fission continued and giant polynucleated cells formed. Later, cell division resumed and cells returned to normal form. In conditioned medium, cytokinesis of the dispersed parasites did not stop. Results indicated that T. foetus cells secreted an extracellular factor that influenced cytokinesis.
