Autophagy flux inhibition mediated by celastrol sensitized lung cancer cells to TRAIL-induced apoptosis via regulation of mitochondrial transmembrane potential and reactive oxygen species

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is well known as a transmembrane cytokine and has been proposed as one of the most effective anti-cancer therapeutic agents, owing to its efficiency to selectively induce cell death in a variety of tumor cells. Suppression of autophagy flux has been increasingly acknowledged as an effective and novel therapeutic intervention for cancer. The present study demonstrated that the anti-cancer and anti-inflammatory drug celastrol, through its anti-metastatic properties, may initiate TRAIL-mediated apoptotic cell death in lung cancer cells. This sensitization was negatively affected by N-acetyl-l-cysteine, which restored the mitochondrial membrane potential (ΔΨm) and inhibited reactive oxygen species (ROS) generation. Notably, treatment with celastrol caused an increase in microtubule-associated proteins 1A/1B light chain 3B-II and p62 levels, whereas co-treatment of celastrol and TRAIL increased active caspase 3 and 8 levels compared with the control, confirming inhibited autophagy flux. The combined use of TRAIL with celastrol may serve as a safe and adequate therapeutic technique for the treatment of TRAIL-resistant lung cancer, suggesting that celastrol-mediated autophagy flux inhibition sensitized TRAIL-initiated apoptosis via regulation of ROS and ΔΨm.