PPARγ activation by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux.

Abstract

Members of the tumor necrosis factor (TNF) transmembrane cytokine superfamily, such as TNFα and Fas ligand (FasL), play crucial roles in inflammation and immunity. TRAIL is a member of this superfamily with the ability to selectively trigger cancer cell death but does not motive cytotoxicity to most normal cells. Troglitazone are used in the cure of type II diabetes to reduce blood glucose levels and improve the sensitivity of an amount of tissues to insulin. In this study, we revealed that troglitazone could trigger TRAIL-mediated apoptotic cell death in human lung adenocarcinoma cells. Pretreatment of troglitazone induced activation of PPARγ in a dose-dependent manner. In addition conversion of LC3-I to LC3-II and PPARγ was suppressed in the presence of GW9662, a well-characterized PPARγ antagonist. Treatment with troglitazone resulted in a slight increase in conversion rate of LC3-I to LC3-II and significantly decreased p62 expression levels in a dose-dependent manner. This indicates that troglitazone induced autophagy flux activation in human lung cancer cells. Inhibition of autophagy flux applying a specific inhibitor and genetically modified ATG5 siRNA enclosed troglitazone-mediated enhancing effect of TRAIL. These data demonstrated that activation of PPARγ mediated by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux and also suggest that troglitazone may be a combination therapeutic target with TRAIL protein in TRAIL-resistant cancer cells.

• Authors: Uddin Md Nazim, Ji-Hong Moon, You-Jin Lee, Jae-Won Seol, Sang-Youel Park
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 16 Pg. 26819-26831 (Apr 18 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28460464 (Publication Type: Journal Article)

Chemical References

• Chromans
• PPAR gamma
• TNF-Related Apoptosis-Inducing Ligand
• Thiazolidinediones
• Troglitazone

Topics

• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Line, Tumor
• Chromans (pharmacology)
• Humans
• Lung Neoplasms (metabolism)
• PPAR gamma (agonists, metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Thiazolidinediones (pharmacology)
• Troglitazone