ArticleFree radical biology & medicine2012
Inhibition of hydrogen peroxide signaling by 4-hydroxynonenal due to differential regulation of Akt1 and Akt2 contributes to decreases in cell survival and proliferation in hepatocellular carcinoma cells.
Article in Free radical biology & medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 40 citations in OpenAlex.
- Alox8 knockout exacerbates imiquimod-induced psoriasis-like inflammation.Cell death & disease · 2026Article
- Comprehensive Analysis of the Role of Heat Shock Proteins in the Immune Microenvironment and Clinical Significance of Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2025Article
- Synthetic Circular RNA for microRNA-1269a Suppresses Tumor Progression in Oral Squamous Cell Carcinoma.Cancers · 2024Article
- Reactive Carbonyl Species and Protein Lipoxidation in Atherogenesis.Antioxidants (Basel, Switzerland) · 2024Review
- Reactive Oxygen Species Bridge the Gap between Chronic Inflammation and Tumor Development.Oxidative medicine and cellular longevity · 2022Review
- Hydroxynonenal Causes Hepatocyte Death by Disrupting Lysosomal Integrity in Nonalcoholic Steatohepatitis.Cellular and molecular gastroenterology and hepatology · 2022Article
- Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury.Experimental & molecular medicine · 2021Review
- Can Medicinal Plants and Bioactive Compounds Combat Lipid Peroxidation Product 4-HNE-Induced Deleterious Effects?Biomolecules · 2020Review
- Targeting allosteric site of AKT by 5,7-dimethoxy-1,4-phenanthrenequinone suppresses neutrophilic inflammation.EBioMedicine · 2019Article
- PLCγ2 promotes apoptosis while inhibits proliferation in rat hepatocytes through PKCD/JNK MAPK and PKCD/p38 MAPK signalling.Cell proliferation · 2018Article
- Article
- 4-hydroxynonenal-mediated signaling and aging.Free radical biology & medicine · 2017Review
- Danshen protects against early-stage alcoholic liver disease in mice via inducing PPARα activation and subsequent 4-HNE degradation.PloS one · 2017Article
- Glutathione peroxidase 4 plays an important role in oxidative homeostasis and wound repair in corneal epithelial cells.FEBS open bio · 2016Article
- 4-Hydroxy-2-nonenal induces apoptosis by activating ERK1/2 signaling and depleting intracellular glutathione in intestinal epithelial cells.Scientific reports · 2016Article
- Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review).International journal of oncology · 2016Review
- Induction of cell cycle arrest and apoptosis in caspase-3 deficient MCF-7 cells by Dillenia suffruticosa root extract via multiple signalling pathways.BMC complementary and alternative medicine · 2014Article
- Identification of 5' AMP-activated kinase as a target of reactive aldehydes during chronic ingestion of high concentrations of ethanol.The Journal of biological chemistry · 2014Article
- An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease.International journal of cell biology · 2014Review
- Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.Oxidative medicine and cellular longevity · 2014Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Dysregulation of cell signaling by electrophiles such as 4-hydroxynonenal (4-HNE) is a key component in the pathogenesis of chronic inflammatory liver disease. Another consequence of inflammation is the perpetuation of oxidative damage by the production of reactive oxidative species such as hydrogen peroxide. Previously, we have demonstrated Akt2 as a direct target of 4-HNE in hepatocellular carcinoma cells. In the present study, we used the hepatocellular carcinoma cell line HepG2 as model to understand the combinatorial effects of 4-HNE and hydrogen peroxide. We demonstrate that 4-HNE inhibits hydrogen peroxide-mediated phosphorylation of Akt1 but not Akt2. Pretreatment of HepG2 cells with 4-HNE prevented hydrogen peroxide stimulation of Akt-dependent phosphorylation of downstream targets and intracellular Akt activity compared with untreated control cells. Using biotin hydrazide capture, it was confirmed that 4-HNE treatment resulted in carbonylation of Akt1, which was not observed in untreated control cells. Using a synthetic GSK3α/β peptide as a substrate, treatment of recombinant human myristoylated Akt1 (rAkt1) with 20 or 40 μΜ 4-HNE inhibited rAkt1 activity by 29 and 60%, respectively. We further demonstrate that 4-HNE activates Erk via a PI3 kinase and PP2A-dependent mechanism leading to increased Jnk phosphorylation. At higher concentrations, 4-HNE decreased both cell survival and proliferation as evidenced by MTT assays and EdU incorporation as well as decreased expression of cyclin D1 and β-catenin, an effect only moderately increased by the addition of hydrogen peroxide. The ability of 4-HNE to exert combinatorial effects on Erk, Jnk, and Akt-dependent cell survival pathways provides additional insight into the mechanisms of cellular damage associated with chronic inflammation.
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Registered trials
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.