RESUMEN
BACKGROUND: Gastric cancer is a common gastrointestinal cancer and currently has the third-highest mortality rate. Research shows that the natural compound narciclasine has a variety of biological activities. The present study aimed to investigate the effect of narciclasine on gastric cancer cells and its molecular mechanisms and determine whether this compound could be a novel therapy for gastric cancer. METHODS: MTT and clone assays were employed to detect the proliferation of gastric cancer cells. The cell apoptosis was detected by flow cytometry. The formation of autophagosomes and autophagosomal lysosomes was observed by transmission electron microscopy and laser confocal scanning microscopy. Western blotting was used to detect the expression of apoptosis, autophagy and Akt/mTOR pathway-related proteins. RESULTS: In this study, we found that narciclasine could inhibit the proliferation of gastric cancer cells and promote apoptosis in gastric cancer cells. Further experiments showed that narciclasine promoted the levels of autophagy proteins LC3-II, Atg-5 and Beclin-1, reduced the expression of the autophagy transporter p62, and increased autophagic flux. By using the autophagy inhibitors 3-MA and CQ, it was shown that narciclasine could induce autophagy-mediated apoptosis in gastric cancer cells. Finally, we found that narciclasine had no significant effects on the total content of Akt and mTOR in gastric cancer cells, and it involved autophagy in gastric cancer cells by reducing the phosphorylation level of p-Akt and p-mTOR. CONCLUSIONS: Narciclasine can induce autophagy-dependent apoptosis in gastric cancer cells by inhibiting the phosphorylation level of Akt/mTOR and thus reduce the proliferation of gastric cancer cells.
Asunto(s)
Alcaloides de Amaryllidaceae/farmacología , Antineoplásicos Fitogénicos/farmacología , Fenantridinas/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Obesity increases the incidence, progression and mortality of breast cancer among postmenopausal females. This is partly due to excessive estrogen production in the adipose tissue of obese females. Aromatase is a key enzyme in estrogen biosynthesis. In the current study, the tensional forcetriggered inducibility of aromatase expression was observed to vary in ASCs isolated from different diseasefree individuals. In addition, this phenomenon was associated with the activation of the aromatase PII promoter and its DNA methylation load. These findings highlight the impact of tensional forces on estrogen biosynthesis in obese females.
Asunto(s)
Tejido Adiposo/enzimología , Aromatasa/metabolismo , Metilación de ADN , Tejido Adiposo/citología , Aromatasa/genética , Azacitidina/análogos & derivados , Azacitidina/farmacología , Técnicas de Cultivo de Célula , Células Cultivadas , Islas de CpG , Decitabina , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Obesidad/metabolismo , Obesidad/patología , Regiones Promotoras Genéticas , ARN Mensajero/metabolismoRESUMEN
Metastasis is the leading cause of cancer-related death in almost all types of cancers, including colorectal cancer (CRC). Metastasis is a complex, multistep, dynamic biological event, and epithelial-mesenchymal transition (EMT) is a critical process during the cascade. Ajuba family proteins are LIM domain-containing proteins and are reported to be transcription repressors regulating different kinds of physiological processes. However, the expression and pathological roles of Ajuba family proteins in tumors, especial in tumor metastasis, remain poorly studied. Here, we found that JUB, but not the other Ajuba family proteins, was highly upregulated in clinical specimens and CRC cell lines. Ectopic expression of JUB induced EMT and enhanced motility and invasiveness in CRC, and vice versa. Mechanistic study revealed that JUB induces EMT via Snail and JUB is also required for Snail-induced EMT. The expression of JUB shows an inverse correlation with E-cadherin expression in clinical specimens. Taken together, these findings revealed that the LIM protein JUB serves as a tumor-promoting gene in CRC by promoting EMT, a critical process of metastasis. Thus, the LIM protein JUB may provide a novel target for therapy of metastatic CRC.