Autophagy In Liver Cancer Cells Research Articles

The suppressive effects of Britannin (Bri) on human liver cancer through inducing apoptosis and autophagy via AMPK activation regulated by ROS

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.

Abstract 3547: CEBPD induces apoptosis through autophagy in metformin-treated HCC

Abstract The patients with hepatocellular carcinoma (HCC) face the risk of cancer relapse or liver dysfunction. Metformin (Met), a first-line drug of type 2 diabetes, has been proved that it could induce G1 arrest and prevent or inhibit HCC. Previously, we demonstrated that the transcription factor CCAAT/enhancer-binding protein delta (CEBPD) plays a tumor suppressor and is responsive to many anticancer drugs in HCC. In this study, we found that Met could induce autophagy, growth arrest and further apoptosis in Huh7 cells. Met enhanced CEBPD expression via stabilizing its protein stability. The loss of CEBPD attenuated the Met-induced autophagy, growth arrest and apoptosis. Importantly, in addition to increasing P27 and down-regulating cyclin D1, CEBPD also contributed the increases of LC3B and ATG3 and LC3 puncta formation. We revealed a novel involvement of CEBPD in Met-induced growth arrest, apoptosis and autophagy of liver cancer cells through regulating p27, cyclinD1, LC3B and ATG3. Citation Format: I P. Lin. CEBPD induces apoptosis through autophagy in metformin-treated HCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3547.