Attenuation of autophagy flux by 6-shogaol sensitizes human liver cancer cells to TRAIL-induced apoptosis via p53 and ROS

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and is an antitumor drug that induces apoptosis in tumor cells with minimal or no effects on normal cells. Here, it is demonstrated that 6-shogaol (6-sho), a bioactive component of ginger, exerted anti-inflammatory and anticancer properties, attenuated tumor cell propagation and induced TRAIL-mediated cell death in liver cancer cells. The current study identified a potential pathway by revealing that TRAIL and 6-sho or chloroquine acted together to trigger reactive oxygen species (ROS) production, to upregulate tumor-suppressor protein 53 (p53) expression and to change the mitochondrial transmembrane potential (MTP). Treatment with N-acetyl-L-cysteine reversed these effects, restoring the MTP and attenuated ROS production and p53 expression. Interestingly, treatment with 6-sho increased p62 and microtubule-associated proteins 1A/1B light chain 3B-II levels, indicating an inhibited autophagy flux. In conclusion, attenuation of 6-sho-induced autophagy flux sensitized cells to TRAIL-induced apoptosis via p53 and ROS, suggesting that the administration of TRAIL in combination with 6-sho may be a suitable therapeutic method for the treatment of TRAIL-resistant Huh7 liver cells.