ArticleCell death & disease2020
GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
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- ERM Inhibition Confers Ferroptosis Resistance through ROS-Induced NRF2 Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Empagliflozin protected kidney function in CKD rat through suppressing hypoxic and fibrotic signalings mediated inflammation and EMT.Histology and histopathology · 2026Article
- Tunneling Nanotube-Mediated Transcellular Autophagy Alleviates Cadmium Induced Hepatocyte Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- NSC632839 suppresses esophageal squamous cell carcinoma cell proliferation in vitro by triggering spindle assembly checkpoint-mediated mitotic arrest and CREB-Noxa-dependent apoptosis.Cancer cell international · 2025Article
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- Engineering exosomes from fibroblast growth factor 1 pre-conditioned adipose-derived stem cells promote ischemic skin flaps survival by activating autophagy.Materials today. Bio · 2024Article
- Necroptosis-based glioblastoma prognostic subtypes: implications for TME remodeling and therapy response.Annals of medicine · 2024Article
- Context-dependent roles for ubiquitous mitochondrial creatine kinase CKMT1 in breast cancer progression.Cell reports · 2024Article
- PMLife (Basel, Switzerland) · 2023Article
- A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.The EMBO journal · 2023Article
- Inhibition of GSK3β activity alleviates acute liver failure via suppressing multiple programmed cell death.Journal of inflammation (London, England) · 2023Article
- Review
- Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease.Pharmaceuticals (Basel, Switzerland) · 2022Article
- The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products.Antioxidants (Basel, Switzerland) · 2022Review
- Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells.Antioxidants (Basel, Switzerland) · 2022Review
- Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases.Medicinal research reviews · 2022Review
- A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma.Frontiers in immunology · 2022Review
- Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms.Frontiers in neuroscience · 2021Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Signaling pathways controlling necrosis are still mysterious and debated. We applied a shRNA-based viability screen to identify critical elements of the necrotic response. We took advantage from a small molecule (G5) that makes covalent adducts with free thiols by Michael addition and elicits multiple stresses. In cells resistant to apoptosis, G5 triggers necrosis through the induction of protein unfolding, glutathione depletion, ER stress, proteasomal impairments, and cytoskeletal stress. The kinase GSK3β was isolated among the top hits of the screening. Using the quinone DMNQ, a ROS generator, we demonstrate that GSK3β is involved in the regulation of ROS-dependent necrosis. Our results have been validated using siRNA and by knocking-out GSK3β with the CRISPR/Cas9 technology. In response to DMNQ GSK3β is activated by serine 9 dephosphorylation, concomitantly to Akt inactivation. During the quinone-induced pro-necrotic stress, GSK3β gradually accumulates into the nucleus, before the collapse of the mitochondrial membrane potential. Accumulation of ROS in response to DMNQ is impaired by the absence of GSK3β. We provide evidence that the activities of the obligatory two-electrons reducing flavoenzymes, NQO1 (NAD(P)H quinone dehydrogenase 1) and NQO2 are required to suppress DMNQ-induced necrosis. In the absence of GSK3β the expression of NQO1 and NQO2 is dramatically increased, possibly because of an increased transcriptional activity of NRF2. In summary, GSK3β by blunting the anti-oxidant response and particularly NQO1 and NQO2 expression, favors the appearance of necrosis in response to ROS, as generated by the quinone DMNQ.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.