Duloxetine Enhances TRAIL-mediated Apoptosis via AMPK-mediated Inhibition of Autophagy Flux in Lung Cancer Cells.

Abstract

BACKGROUND/AIM:

The antidepressant duloxetine is known as a serotonin-norepinephrine reuptake inhibitor, used for treating depression and anxiety. TRAIL selectively induces cell death in a variety of tumor cells by binding to its membrane death receptor (DR). The aim of the study was to examine whether duloxetine affects TRAIL-mediated apoptosis.

MATERIALS AND METHODS:

Cell viability and apoptosis was measured by morphological image, crystal violet staining, MTT and LDH assay. Immunocytochemistry and western blotting techniques were applied to detect autophagy and apoptosis indicator proteins. TEM assay was used to determine the autophagy.

RESULTS:

Duloxetine treatment considerably sensitizes human lung adenocarcinoma cells to TRAIL-mediated apoptosis by targeting TRAIL-DR5. Treatment with duloxetine inhibited AMPK phosphorylation and resulted in increased p62 and microtubule-associated protein 1A/1B light chain 3B-II levels, indicating inhibition of autophagy flux. Blockade of DR5 with DR5-specific small-interfering RNA negatively regulated the apoptotic effect.

CONCLUSION:

Clinical administration of TRAIL in combination with duloxetine may serve as a therapeutic approach for the treatment of TRAIL-resistant lung cancer cells.

• Authors: K M A Zinnah, Sang-Youel Park
• Journal: Anticancer research (Anticancer Res) Vol. 39 Issue 12 Pg. 6621-6633 (Dec 2019) ISSN: 1791-7530 [Electronic] Greece
• PMID: 31810927 (Publication Type: Journal Article)
• Copyright: Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• MAP1LC3A protein, human
• MAP1LC3B protein, human
• Microtubule-Associated Proteins
• P62 protein, human
• RNA, Small Interfering
• RNA-Binding Proteins
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Serotonin and Noradrenaline Reuptake Inhibitors
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10B protein, human
• TNFSF10 protein, human
• Duloxetine Hydrochloride
• L-Lactate Dehydrogenase
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Apoptosis (drug effects)
• Autophagic Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Duloxetine Hydrochloride (pharmacology)
• Humans
• L-Lactate Dehydrogenase (metabolism)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Microtubule-Associated Proteins (metabolism)
• Phosphorylation (drug effects)
• RNA, Small Interfering
• RNA-Binding Proteins (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (antagonists & inhibitors, metabolism)
• Serotonin and Noradrenaline Reuptake Inhibitors (pharmacology)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Up-Regulation