RESUMEN
Helioxanthin, an active compound from Taiwania cryptomerioides Hayata, has been shown to have various biological activities. However, their anticancer effect in oral squamous cell carcinoma has not been well established yet. Helioxanthin inhibited the proliferation of oral squamous cell carcinoma cells in a dose-dependent manner by inducing G2/M phase arrest. Similarly, helioxanthin inhibited cyclooxygenase-2, (COX-2), phosphorylated EGFR, and extracellular-signal-regulated kinases (ERK) protein level and further reduced the nuclear accumulation of phosphorylated epidermal growth factor receptor (pEGFR) and activator protein-1(AP-1) family protein, c-fos. Moreover, helioxanthin at the dose of 20 and 30 mg kg-1 for 15 days reduced the tumor growth in animal model. This study demonstrated that Helioxanthin exerts its anticancer activity against oral cancer cells by downregulating EGFR/ERK/c-fos signaling pathway to inhibit COX-2 level and by activating cyclin-dependent kinase inhibitor (p27) to further induce G2/M cell cycle arrest. This helioxanthin may serve as a novel candidate for oral cancer prevention. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 2045-2056, 2016.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Lignanos/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Arecolina , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Xenoinjertos , Lignanos/uso terapéutico , Sistema de Señalización de MAP Quinasas , Masculino , Ratones Desnudos , Neoplasias de la Boca/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Transcripción AP-1/metabolismoRESUMEN
The aim of our study was to investigate the mechanisms by which rhubarb regulates ß-catenin as well as metastasis of hepatocellular carcinomas. Our results revealed that rhubarb extract inhibited HA22T cell migration ability in wound healing, migration and invasion assays in a dose-dependent manner. Rhubarb also reduced ß-catenin protein level, downregulated its downstream proteins, cyclin D, Tbx3 and c-Myc, and attenuated the expression of MMP9 and contactin-1 metastatic factors. Additionally, rhubarb inhibited ß-catenin nuclear accumulation and induced its degradation via proteasome-mediated pathway. Furthermore, we found that rhubarb suppressed the p-ser(9) GSK-3-ß protein level to inactivate Wnt signalling and reduce ß-catenin protein level. Taken together; we found that rhubarb blocked the metastatic process of HA22T hepatocellular carcinoma cells mediated through GSK-3-ß activation, and enhancement of protein degradation as well as reduction of the nuclear accumulation of ß-catenin.