RESUMEN
Salt-inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial-mesenchymal transition via inhibition of AKT/GSK3ß/ß-catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3ß/ß-catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.
Asunto(s)
Autofagia , Fosfoproteínas Fosfatasas/metabolismo , Proteína Fosfatasa 2/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteolisis , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Animales , Línea Celular Tumoral , Estudios de Cohortes , Regulación hacia Abajo/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Modelos Biológicos , Fenotipo , Fosfoproteínas Fosfatasas/genética , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/genética , Regulación hacia Arriba/genética , beta Catenina/metabolismoRESUMEN
The aim of the study was to investigate the anti-proliferation and apoptosis-inducing effects of S1, a novel tetrandrine derivative, in human gastric cancer BGC-823 cells and explore the possible mechanism of action. The anti-proliferative activity was determined by MTT assay; the induction of cell cycle arrest and apoptosis were detected by flow cytometry. Quantitative real time RT-PCR and Western blotting were used to evaluate the mRNA and protein expression levels in mitochondrial pathway. S1 significantly reduced cell viability and induced a G2/M phase arrest and apoptosis in dose- and time-dependent manner. Further studies showed that S1 increased mRNA and protein expression of Bax and the Bax/Bcl-2 ratio. Moreover, S1 decreased the protein expression of procaspase-9 and procaspase-3, suggesting that the induction of apoptosis may be related to the alteration of the ratio of Bax/Bcl-2 and the activation of caspases. These findings suggested that S1 merits further investigation as a novel therapeutic agent for the treatment of human gastric cancer.