ArticleAutophagy2011
zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation.
Article in Autophagy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed.
- α-Synuclein Degradation in Brain Pericytes Is Mediated via Akt, ERK, and p38 MAPK Signaling Pathways.International journal of molecular sciences · 2025Article
- Liquid-liquid phase separation: an emerging perspective on the tumorigenesis, progression, and treatment of tumors.Frontiers in immunology · 2025Review
- The Interplay Between Autophagy and Regulated Necrosis.Antioxidants & redox signaling · 2023Review
- Inhibition of Autophagy Promotes the Anti-Tumor Effect of Metformin in Oral Squamous Cell Carcinoma.Cancers · 2022Article
- Off-target inhibition of NGLY1 by the polycaspase inhibitor Z-VAD-fmk induces cellular autophagy.The FEBS journal · 2022Article
- Pan-Caspase Inhibitor zVAD Induces Necroptotic and Autophagic Cell Death in TLR3/4-Stimulated Macrophages.Molecules and cells · 2022Article
- Cadmium Impairs Autophagy Leading to Apoptosis by CaNeurochemical research · 2021Article
- Autophagy modulation altered differentiation capacity of CD146Stem cell research & therapy · 2020Article
- Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells.Journal of Cancer · 2020Article
- Synthesis of Chalcone Derivatives: Inducing Apoptosis of HepG2 CellsFrontiers in pharmacology · 2019Article
- Temporal Pattern and Crosstalk of Necroptosis Markers with Autophagy and Apoptosis Associated Proteins in Ischemic Hippocampus.Neurotoxicity research · 2018Article
- TAK1 mediates excessive autophagy via p38 and ERK in cisplatin-induced acute kidney injury.Journal of cellular and molecular medicine · 2018Article
- Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium.The Journal of experimental medicine · 2017Article
- A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up-regulation in gastric cancer cells.Scientific reports · 2017Article
- Vibrio cholerae Cholix Toxin-Induced HepG2 Cell Death is Enhanced by Tumor Necrosis Factor-Alpha Through ROS and Intracellular Signal-Regulated Kinases.Toxicological sciences : an official journal of the Society of Toxicology · 2017Article
- Blocking TCR restimulation induced necroptosis in adoptively transferred T cells improves tumor control.Oncotarget · 2016Article
- Article
- Vibrio vulnificus VvhA induces autophagy-related cell death through the lipid raft-dependent c-Src/NOX signaling pathway.Scientific reports · 2016Article
- CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins.Scientific reports · 2015Article
- TAK1 inhibition-induced RIP1-dependent apoptosis in murine macrophages relies on constitutive TNF-α signaling and ROS production.Journal of biomedical science · 2015Article
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6 authors.
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No grant is acknowledged in the PubMed record.
Abstract
The treatment of L929 fibrosarcoma cells with zVAD has been shown to induce necroptosis. However, whether autophagy is involved or not in this event remains controversial. In this study, we re-examined the role of autophagy in zVAD-induced cell death in L929 cells and further elucidated the signaling pathways triggered by caspase inhibition and contributing to autophagic death. First, we found that zVAD can stimulate LC3-II formation, autophagosome and autolysosome formation, and ROS accumulation. Antioxidants, beclin 1 or Atg5 silencing, and class III PtdIns3K inhibitors all effectively blocked ROS production and cell death, suggesting ROS accumulation downstream of autophagy contributes to cell necrosis. zVAD also stimulated PARP activation, and the PARP inhibitor DPQ can reduce zVAD-induced cell death, but did not affect ROS production, suggesting the increased ROS leads to PARP activation and cell death. Notably, our data also indicated the involvement of Src-dependent JNK and ERK in zVAD-induced ROS production and autophagic death. We found caspase 8 is associated with c-Src at the resting state, and upon zVAD treatment this association was decreased and accompanied by c-Src activation. In conclusion, we confirm the autophagic death in zVAD-treated L929 cells, and define a new molecular pathway in which Src-dependent ERK and JNK activation can link a signal from caspase inhibition to autophagy, which in turn induce ROS production and PARP activation, eventually leading to necroptosis. Thus, in addition to initiating proteolytic activity for cell apoptosis, inactivated caspase 8 also functions as a signaling molecule for autophagic death.
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