The suppressive effects of Britannin (Bri) on human liver cancer through inducing apoptosis and autophagy via AMPK activation regulated by ROS
| Autor: | Fan Zhang, Yan-Jun Liu, Yong-Qiang Cui |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
ATG5 Biophysics Apoptosis AMP-Activated Protein Kinases Biochemistry Cell Line Lactones 03 medical and health sciences Cell Line Tumor Autophagy Humans Molecular Biology Mechanistic target of rapamycin PI3K/AKT/mTOR pathway chemistry.chemical_classification Reactive oxygen species biology Chemistry Liver Neoplasms AMPK Cell Biology Antineoplastic Agents Phytogenic Cell biology Enzyme Activation 030104 developmental biology Cancer cell biology.protein Inula Reactive Oxygen Species Sesquiterpenes |
| Zdroj: | Biochemical and Biophysical Research Communications. 497:916-923 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2017.12.144 |
| Popis: | Britannin (Bri), isolated from Inula aucheriana, is a sesquiterpene lactone (SL), a class of secondary metabolites. Previous studies have suggested the anti-cancer potential of Bri; however, the molecular mechanism remains elusive. The present study investigated the effects of Bri on liver cancer progression. Our findings indicated that Bri significantly suppressed the growth of liver cancer cell lines. Mechanistic researches revealed that Bri induced apoptosis through the extrinsic and intrinsic apoptotic pathways, as evidenced by the increase of Caspase-8, -9 and -3 cleavages. In addition, Bri-triggered autophagy in liver cancer cells, supported by the up-regulation of light chain 3 (LC3) II, p62, autophagy-related 5 (ATG5) and Beclin 1, as well as the occurrence of autophagic vacuoles. Importantly, Bri increased AMPK activation, while decreased the activity of its down-streaming signal, mTOR. Of note, suppression of AMP-activated protein kinase (AMPK) activation using its inhibitor, Compound C, could inhibit both apoptosis and autophagy induced by Bri. Furthermore, Bri was found to induce reactive oxygen species (ROS) generation in hepatic cancer cells. Notably, reducing ROS production by its scavenger, N-acetyl cysteine (NAC), could down-regulate p-AMPK levels, while up-regulate the phosphorylated mechanistic target of rapamycin (p-mTOR) expressions, accompanied with the restored cell viability, as well as the reduced apoptosis and autophagy in Bri-treated liver cancer cells. Finally, Bri inhibited the tumor growth in vivo without side effects. In conclusion, our study illustrated that Bri could induce apoptosis and autophagy by activating AMPK regulated by ROS in liver cancer cells, supplying molecular bases for developing Bri into an effective candidate against liver cancer. |
| Databáze: | OpenAIRE |
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