Cited by 28Autophagy in Disease and TherapyEndoplasmic Reticulum Stress and DiseaseRedox biology and oxidative stress

Inhibiting Lysine 353 Oxidation of GRP78 by a Hypochlorous Probe Targeting Endoplasmic Reticulum Promotes Autophagy in Cancer Cells

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Ning, Junya, Lin, Zhaomin, Zhao, Xuan, Zhao, Baoxiang, Miao, Junying·2019·Cell Death & Disease

Abstract

The level of hypochlorous acid (HOCl) in cancer cells is higher than that in non-cancer cells. HOCl is an essential signal for the regulation of cell fate and works mainly through the protein post-translational modifications in cancer cells. However, the mechanism of HOCl regulating autophagy has not been clarified. Here we reported that a HOCl probe named ZBM-H targeted endoplasmic reticulum and induced an intact autophagy flux in lung cancer cells. Furthermore, ZBM-H promoted the binding of GRP78 to AMPK and increased the phosphorylation of AMPK in a dose- and time-dependent manner. GRP78 knockdown inhibited ZBM-H-induced AMPK phosphorylation and ZBM-H-stimulated autophagy. In addition, mass spectrometry combined with point mutation experiments revealed that ZBM-H increased GRP78 activity by inhibiting HOCl-induced lysine 353 oxidation of GRP78. Following ZBM-H treatment in vitro and in vivo, cell growth was significantly inhibited while apoptosis was induced. Nevertheless, exogenous HOCl partially reversed ZBM-H-inhibited cell growth and ZBM-H-induced GRP78 activation. In brief, we found that an endoplasmic reticulum-targeted HOCl probe named ZBM-H, acting through attenuating HOCl-induced GRP78 oxidation, inhibited tumor cell survival by promoting autophagy and apoptosis. Overall, these data demonstrated a novel mechanism of hypochlorous acid regulating autophagy by promoting the oxidation modification of GRP78.

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Authors
Ning, J., Lin, Z., Zhao, X., Zhao, B., & Miao, J.
Affiliations
Shandong University (CN)
Venue
Cell Death & Disease
Published
2019-11-12
Volume
10
Issue
11
Pages
858-858
ISSN
2041-4889 (ISSN-L)
OpenAlex
W2988860320
Cited by
28
References
49
Citations by year
2026: 2 · 2025: 6 · 2024: 3 · 2023: 2 · 2022: 9 · 2021: 5 · 2020: 1
FWCI
2.85
Type
journal article
Language
en
Open access
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (31870831, 31741083, 31871407)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
hypochlorous acid, GRP78, autophagy, AMPK phosphorylation, lung cancer, apoptosis, protein oxidation, tumor cell growth inhibition
MeSH terms
A549 Cells, AMP-Activated Protein Kinase Kinases, Endoplasmic Reticulum Chaperone BiP, Autophagy, Cell Survival, Endoplasmic Reticulum, Heat-Shock Proteins, Humans, Hypochlorous Acid, Lung Neoplasms, Oxidation-Reduction, Phosphorylation, Protein Kinases, Signal Transduction, Apoptosis, Cell Lineage, Endoplasmic Reticulum Stress

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