Imiquimod-induced autophagy is regulated by ER stress-mediated PKR activation in cancer cells

Shu Hao Chang, Shi Wei Huang, Sin Ting Wang, Kai Cheng Chung, Chia Wei Hsieh, Jun Kai Kao, Yi Ju Chen, Chun Ying Wu*, Jeng Jer Shieh

*此作品的通信作者

研究成果: Article同行評審

21 引文 斯高帕斯(Scopus)

摘要

Background Autophagy is a highly conserved cellular catabolic pathway for degradation and recycling of intracellular components in response to nutrient starvation or environmental stress. Endoplasmic reticulum (ER) homeostasis can be disturbed by physiological and pathological influences, resulting in accumulation of misfolded and unfolded proteins in the ER lumen, a condition referred to as ER stress. Imiquimod (IMQ), a Toll-like receptor (TLR) 7 ligand, possesses anti-tumor and anti-viral activities in vitro and in vivo. Objective IMQ has been reported to promote the apoptosis of THP-1-derived macrophages through an ER stress-dependent pathway. However, the role of ER stress in IMQ-induced autophagy is unknown. In this study, we investigated the relationship between ER stress and IMQ-induced autophagy. Methods The expression of LC3, P62, p-PERK, Grp78, p-elF2α and IRE1α proteins were determined by immunoblotting. The relationship between ER stress and IMQ-induced autophagy were analyzed by ER stress inhibitors, a PERK inhibitor and the genetic silencing of PERK. The role of double-strand RNA-dependent protein kinase (PKR) activation in IMQ-induced autophagy was assessed by inhibiting PKR and genetically silencing PKR. The IMQ-induced autophagy was evaluated by immunoblotting and EGFP-LC3 puncta formation. Results IMQ induced reactive oxygen species (ROS) production in cancer cells. Additionally, IMQ markedly induced ER stress via ROS production and increased autophagosome formation in a dose- and time-dependent manner in both TLR7/8-expressing and TLR7/8-deficient cancer cells. Pharmacological or genetic inhibition of ER stress dramatically reduced LC3-II expression and EGFP-LC3 puncta formation in IMQ-treated cancer cells. IMQ-induced autophagy was markedly reduced by depletion and/or inhibition of PKR, a downstream effector of ER stress. Conclusion IMQ-induced autophagy is dependent on PKR activation, which is mediated by ROS-triggered ER stress. These findings might provide useful information for basic research and for the clinical application of IMQ.

原文English
頁(從 - 到)138-148
頁數11
期刊Journal of Dermatological Science
87
發行號2
DOIs
出版狀態Published - 8月 2017

指紋

深入研究「Imiquimod-induced autophagy is regulated by ER stress-mediated PKR activation in cancer cells」主題。共同形成了獨特的指紋。

引用此