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

Abstract：

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.

journal_name

J Dermatol Sci

journal_title

Journal of dermatological science

authors

Chang SH,Huang SW,Wang ST,Chung KC,Hsieh CW,Kao JK,Chen YJ,Wu CY,Shieh JJ

doi

10.1016/j.jdermsci.2017.04.011

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

138-148

issue

eissn

0923-1811

issn

1873-569X

pii

S0923-1811(16)30896-9

journal_volume

pub_type

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