RESUMEN
Our previous study showed that TP53-induced glycolysis and apoptosis regulator (TIGAR) regulated ROS, autophagy, and apoptosis in response to hypoxia and chemotherapeutic drugs. Aescin, a triterpene saponin, exerts anticancer effects and increases ROS levels. The ROS is a key upstream signaling to activate autophagy. Whether there is a crosstalk between TIGAR and aescin in regulating ROS, autophagy, and apoptosis is unknown. In this study, we found that aescin inhibited cell viability and colony formation, and induced DNA damage, cell cycle arrest, and apoptosis in cancer cell lines HCT-116 and HCT-8 cells. Concurrently, aescin increased the expression of TIGAR, ROS levels, and autophagy activation. Knockdown of TIGAR enhanced the anticancer effects of aescin in vitro and in vivo, whereas overexpression of TIGAR or replenishing TIGAR downstream products, NADPH and ribose, attenuated aescin-induced apoptosis. Furthermore, aescin-induced ROS elevation and autophagy activation were further strengthened by TIGAR knockdown in HCT-116 cells. However, autophagy inhibition by knockdown of autophagy-related gene ATG5 or 3-methyladenine (3-MA) exaggerated aescin-induced apoptosis when TIGAR was knocked down. In conclusion, TIGAR plays a dual role in determining cancer cell fate via inhibiting both apoptosis and autophagy in response to aescin, which indicated that inhibition of TIGAR and/or autophagy may be a junctional therapeutic target in treatment of cancers with aescin.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Escina/farmacología , Péptidos y Proteínas de Señalización Intracelular/genética , Animales , Proteínas Reguladoras de la Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Desnudos , Monoéster Fosfórico Hidrolasas , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Many diseases have been associated with intestinal microbial dysbiosis. Host-microbial interactions regulate immune function, which influences the development of gastric cancer. AIMS: The aims were to investigate the characteristics of intestinal microbiota composition in gastric cancer patients and correlations between the intestinal microbiota and cellular immunity. METHODS: Fecal samples were collected from 116 gastric cancer patients and 88 healthy controls from Shanxi Province, China. The intestinal microbiota was investigated by 16S rRNA gene sequencing. Peripheral blood samples were also collected from the 66 gastric cancer patients and 46 healthy controls. The populations of peripheral T lymphocyte subpopulations and NK cells were analyzed by flow cytometry. RESULTS: The intestinal microbiota in gastric cancer patients was characterized by increased species richness, decreased butyrate-producing bacteria, and the enrichment of other symbiotic bacteria, especially Lactobacillus, Escherichia, and Klebsiella. Lactobacillus and Lachnospira were key species in the network of gastric cancer-associated bacterial genera. The combination of the genera Lachnospira, Lactobacillus, Streptococcus, Veillonella, and Tyzzerella_3 showed good performance in distinguishing gastric cancer patients from healthy controls. There was no significant difference in enterotype distribution between healthy controls and gastric cancer patients. The percentage of CD3+ T cells was positively correlated with the abundance of Lactobacillus and Streptococcus, and CD3+ T cells, CD4+ T cells, and NK cells were associated with Lachnospiraceae taxa. CONCLUSIONS: Our study revealed a dysbiotic intestinal microbiota in gastric cancer patients. The abundance of some intestinal bacterial genera was correlated with the population of peripheral immune cells.