Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential target for cancer therapy, owing to its ability to selectively kill cancer cells without causing significant toxicity to normal cells. However, due to the lack of death receptor expression, cancer cells can become highly resistant to TRAIL. Hence, it is vital to develop agents that restore TRAIL efficacy. Sertraline is an antidepressant drug with anticancer properties. To the best of our knowledge, this is the first study to demonstrate that sertraline inhibits autophagic flux and increases the expression of death receptor 5 (DR5) on TRAIL-resistant lung cancer cells. Inhibition of autophagy using autophagy inhibitors 3-methyladenine and chloroquine upregulated the expression of DR5 and enhanced TRAIL-induced apoptosis, as confirmed by the increase of pro-apoptotic proteins caspase-8 and caspase-3. Silencing DR5 expression using DR5 small interfering RNA prevented sertraline-induced TRAIL-mediated apoptosis, indicating the role of DR5 in TRAIL-mediated apoptosis. Overall, sertraline enhanced TRAIL-mediated apoptosis via the downregulation of AMP-activated protein kinase phosphorylation, resulting in the inhibition of autophagic flux, upregulation of DR5 expression, and activation of the apoptotic caspase cascade. These data suggested that sertraline could be used to sensitize human lung cancer cells to TRAIL, while also serving as a therapeutic option in cancer patients with depression.