ABSTRACT
Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system, and Chinese herbal medicine plays an important role in tumor treatment. The in-depth study of auriculasin isolated from Flemingia philippinensis showed that auriculasin promoted reactive oxygen species (ROS) generation in a concentration-dependent manner; when ROS scavenger NAC was added, the effects of auriculasin in promoting ROS generation and inhibiting cell viability were blocked. Auriculasin induced CRC cell apoptosis, led to mitochondrial shrinkage, and increased the intracellular accumulation of Fe2+ and MDA. When auriculasin and NAC were added simultaneously, the levels of apoptosis, Fe2+ and MDA returned to the control group levels, indicating that auriculasin activated apoptosis and ferroptosis by inducing ROS generation. In addition, auriculasin promoted the expression of Keap1 and AIFM1, but significantly reduced the phosphorylation level of AIFM1, while NAC significantly blocked the regulation of Keap1 and AIFM1 by auriculasin, which indicates that auriculasin can also induce oxeiptosis through ROS. When Z-VAD-FMK, Ferrostatin-1, Keap1 siRNA, PGAM5 siRNA and AIFM1 siRNA were added respectively, the inhibitory effect of auriculasin on cell viability was significantly weakened, indicating that auriculasin inhibits cell viability by inducing apoptosis, ferroptosis and oxeiptosis. Auriculasin also inhibited the invasion and clone forming ability of CRC cells, while NAC blocked the above effects of auriculasin. Therefore, auriculasin can promote CRC cell apoptosis, ferroptosis and oxeiptosis by inducing ROS generation, thereby inhibiting cell viability, invasion and clone formation, indicating that auriculasin has a significant antitumor effect.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Ferroptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Isoflavones/pharmacology , Reactive Oxygen Species/agonists , Antineoplastic Agents, Phytogenic/isolation & purification , Apoptosis/genetics , Apoptosis Inducing Factor/genetics , Apoptosis Inducing Factor/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Fabaceae/chemistry , Ferroptosis/genetics , HCT116 Cells , Humans , Iron/agonists , Iron/metabolism , Isoflavones/isolation & purification , Kelch-Like ECH-Associated Protein 1/genetics , Kelch-Like ECH-Associated Protein 1/metabolism , Malondialdehyde/agonists , Malondialdehyde/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Models, Biological , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/metabolism , Plant Extracts/chemistry , Reactive Oxygen Species/metabolismABSTRACT
Bisphenol A (BPA) is an important industrial raw material. Because of its widespread use and increasing release into environment, BPA has become a new environmental pollutant. Previous studies about BPA's effects in plants focus on a certain growth stage. However, the plant's response to pollutants varies at different growth stages. Therefore, in this work, BPA's effects in soybean roots at different growth stages were investigated by determining the reactive oxygen species levels, membrane lipid fatty acid composition, membrane lipid peroxidation, and antioxidant systems. The results showed that low-dose BPA exposure slightly caused membrane lipid peroxidation but didn't activate antioxidant systems at the seedling stage, and this exposure did not affect above process at other growth stages; high-dose BPA increased reactive oxygen species levels and then caused membrane lipid peroxidation at all growth stages although it activated antioxidant systems, and these effects were weaker with prolonging the growth stages. The recovery degree after withdrawal of BPA exposure was negatively related to BPA dose, but was positively related to growth stage. Taken together, the effects of BPA on antioxidant systems in soybean roots were associated with BPA exposure dose and soybean growth stage.