RESUMEN
Colorectal cancer (CRC) is the third most commonly diagnosed cancer. Celastrol exhibits anti-tumor activities in a variety of cancers. However, the effect of Celastrol on human CRC and the underlying mechanisms still need to be elucidated. The present study aimed to use in vitro and in vivo methods to clarify the anti-tumor effect of Celastrol and use protein microarrays to explore its mechanisms. We demonstrated that Celastrol effectively inhibited SW480 CRC cell proliferation. Two weeks of Celastrol gavage significantly inhibited the growth of xenografts in nude mice. A total of 69 candidate proteins were identified in the protein microarray experiment, including the most highly enriched protein Shoc2, which is a scaffold protein that modulates cell motility and metastasis through the ERK pathway. Celastrol significantly inhibited ERK1/2 phosphorylation in cell lines and xenograft tumors. Down-regulation of Shoc2 expression using Shoc2 siRNA also inhibited ERK1/2 phosphorylation. Furthermore, down-regulation of Shoc2 expression also significantly inhibited proliferation, colony formation, and migration functions of tumor cells. In addition, the LD0 of Celastrol by gavage is equal or more than 80 mg/kg in C57 male mice. In summary, we unraveled the anti-CRC function of Celastrol and confirmed for the first time that it inhibited the ERK1/2 pathway through binding to Shoc2.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/genética , Triterpenos/administración & dosificación , Animales , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Triterpenos Pentacíclicos , Análisis por Matrices de Proteínas , Unión Proteica/genética , ARN Interferente Pequeño/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The cholinergic anti-inflammatory pathway (CAP) is a new neurophysiologic mechanism regulating the immune system, with alpha7 nicotinic acetylcholine receptor (α7nAChR) being its potential pharmacological target. Cumulative studies have demonstrated that activation of α7nAChR can inhibit inflammation through modulating pro-inflammatory cytokines. The role of α7nAChR has been confirmed in a series of inflammatory diseases. This review is aimed to provide new insights for using a7nAChR against inflammatory diseases.
