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Endoplasmic reticulum stress-dependent autophagy inhibits glycated high-density lipoprotein-induced macrophage apoptosis by inhibiting CHOP pathway.

ABSTRACT: This study was designed to explore the inductive effect of glycated high-density lipoprotein (gly-HDL) on endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-mediated macrophage apoptosis and its relationship with autophagy. Our results showed that gly-HDL caused macrophage apoptosis with concomitant activation of ER stress pathway, including nuclear translocation of activating transcription factor 6, phosphorylation of protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2?, and CHOP up-regulation, which were inhibited by 4-phenylbutyric acid (PBA, an ER stress inhibitor) and the gene silencing of PERK and CHOP. Similar data were obtained from macrophages treated by HDL isolated from diabetic patients. Gly-HDL induced macrophage autophagy as assessed by up-regulation of beclin-1, autophagy-related gene 5 and microtubule-associated protein one light chain 3-II, which were depressed by PBA and PERK siRNA. Gly-HDL-induced apoptosis, PERK phosphorylation and CHOP up-regulation were suppressed by rapamycin (an autophagy inducer), whereas aggravated by 3-methyladenine (an autophagy inhibitor) and beclin-1 siRNA. Administration of diabetic apoE-/- mice with rapamycin attenuated MOMA-2 and CHOP up-regulation and apoptosis in atherosclerotic lesions. These data indicate that gly-HDL may induce macrophage apoptosis through activating ER stress-CHOP pathway and ER stress mediates gly-HDL-induced autophagy, which in turn protects macrophages against apoptosis by alleviating CHOP pathway.

SUBMITTER: Tian H

PROVIDER: S-EPMC6433656 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum stress-dependent autophagy inhibits glycated high-density lipoprotein-induced macrophage apoptosis by inhibiting CHOP pathway.

Tian Hua H Li Yanyan Y Kang Panpan P Wang Zhichao Z Yue Feng F Jiao Peng P Yang Nana N Qin Shucun S Yao Shutong S

Journal of cellular and molecular medicine 20190212 4

This study was designed to explore the inductive effect of glycated high-density lipoprotein (gly-HDL) on endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-mediated macrophage apoptosis and its relationship with autophagy. Our results showed that gly-HDL caused macrophage apoptosis with concomitant activation of ER stress pathway, including nuclear translocation of activating transcription factor 6, phosphorylation of protein kinase-like ER kinase (PERK) and eukaryotic translatio ...[more]

PMID: 30746902

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Project description:Endoplasmic reticulum (ER) is a central organelle in eukaryotic cells that regulates protein synthesis and maturation. Perturbation of ER functions leads to ER stress, which has been previously associated with a broad variety of diseases. ER stress is generally regarded as compensatory, but prolonged ER stress has been involved in apoptosis induced by several cytotoxic agents. Choline kinase α (ChoKα), the first enzyme in the Kennedy pathway, is responsible for the generation of phosphorylcholine (PCho) that ultimately renders phosphatidylcholine. ChoKα overexpression and high PCho levels have been detected in several cancer types. Inhibition of ChoKα has demonstrated antiproliferative and antitumor properties; however, the mechanisms underlying these activities remain poorly understood. Here, we demonstrate that ChoKα inhibitors (ChoKIs), MN58b and RSM932A, induce cell death in cancer cells (T47D, MCF7, MDA-MB231, SW620 and H460), through the prolonged activation of ER stress response. Evidence of ChoKIs-induced ER stress includes enhanced production of glucose-regulated protein, 78 kDa (GRP78), protein disulfide isomerase, IRE1α, CHOP, CCAAT/enhancer-binding protein beta (C/EBPβ) and TRB3. Although partial reduction of ChoKα levels by small interfering RNA was not sufficient to increase the production of ER stress proteins, silencing of ChoKα levels also show a decrease in CHOP overproduction induced by ChoKIs, which suggests that ER stress induction is due to a change in ChoKα protein folding after binding to ChoKIs. Silencing of CHOP expression leads to a reduction in C/EBPβ, ATF3 and GRP78 protein levels and abrogates apoptosis in tumor cells after treatment with ChoKIs, suggesting that CHOP maintains ER stress responses and triggers the pro-apoptotic signal. Consistent with the differential effect of ChoKIs in cancer and primary cells previously described, ChoKIs only promoted a transient and moderated ER stress response in the non-tumorogenic cells MCF10A. In conclusion, pharmacological inhibition of ChoKα induces cancer cell death through a mechanism that involves the activation of exaggerated and persistent ER stress supported by CHOP overproduction.

Dataset Information

Endoplasmic reticulum stress-dependent autophagy inhibits glycated high-density lipoprotein-induced macrophage apoptosis by inhibiting CHOP pathway.

Publications

Endoplasmic reticulum stress-dependent autophagy inhibits glycated high-density lipoprotein-induced macrophage apoptosis by inhibiting CHOP pathway.

Similar Datasets

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