ArticleThe Journal of biological chemistry2019
Indomethacin impairs mitochondrial dynamics by activating the PKCζ-p38-DRP1 pathway and inducing apoptosis in gastric cancer and normal mucosal cells.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 85 citations in OpenAlex.
- Roles of mitochondrial fusion and fission in breast cancer progression: a systematic review.World journal of surgical oncology · 2022Pooled it
- New Functions of Mitochondrial Dysfunction in Gastric Cancer: From Molecular Processes to Potential Treatments.International journal of molecular sciences · 2026Review
- A comparative study of some NSAIDs with natural products: integrating in vitro anticancer efficacy, in vivo antiulcerative effect, histochemistry, and in silico analysis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Mitochondrial Dysfunction as a Targetable Vulnerability in Gastric Cancer: From Carcinogenesis to Apoptosis (A Narrative Review).Journal of Cancer · 2026Review
- The Expendables: Overlooked Medications with Anti-Cancer Properties.Current oncology reports · 2025Review
- Old drugs, new challenges: reassigning drugs for cancer therapies.Cellular & molecular biology letters · 2025Review
- The role of mitochondrial biogenesis, mitochondrial dynamics and mitophagy in gastrointestinal tumors.Cancer cell international · 2025Review
- The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria.Cellular and molecular life sciences : CMLS · 2025Review
- Mechanistic insights into promotion of non-small cell lung cancer by BAG5 using integrative multi-omics approaches.Frontiers in immunology · 2025Article
- Targeting FCRLA to induce necrosis in lung adenocarcinoma: a novel strategy for prognosis and therapy via MPT-Driven pathways.Frontiers in immunology · 2025Article
- Integrated approach to reducing polypharmacy in older people: exploring the role of oxidative stress and antioxidant potential therapy.Redox report : communications in free radical research · 2024Review
- A Comprehensive Pan-Cancer Analysis of Cytochrome C Oxidase Assembly Factor 1 (COA1) Reveals Instrumental Role of Mitochondrial Protein Assembly in Cancer that Modulates Disease Progression and Prognostic Outcome.Cell biochemistry and biophysics · 2024Article
- Guanxin V alleviates ventricular remodeling after acute myocardial infarction with circadian disruption by regulating mitochondrial dynamics.Sleep & breathing = Schlaf & Atmung · 2024Article
- NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death.iScience · 2024Article
- Energy metabolism: a new target for gastric cancer treatment.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2024Review
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- Predicting molecular mechanism of silymarin-potentiated diclofenac toxicity: Insight fromToxicology reports · 2023Article
- Flavonoid-RichInternational journal of molecular sciences · 2023Article
- Repurposing approved non-oncology drugs for cancer therapy: a comprehensive review of mechanisms, efficacy, and clinical prospects.European journal of medical research · 2023Review
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The subcellular mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in gastric cancer and normal mucosal cells is elusive because of the diverse cyclooxygenase-independent effects of these drugs. Using human gastric carcinoma cells (AGSs) and a rat gastric injury model, here we report that the NSAID indomethacin activates the protein kinase Cζ (PKCζ)-p38 MAPK (p38)-dynamin-related protein 1 (DRP1) pathway and thereby disrupts the physiological balance of mitochondrial dynamics by promoting mitochondrial hyper-fission and dysfunction leading to apoptosis. Notably, DRP1 knockdown or SB203580-induced p38 inhibition reduced indomethacin-induced damage to AGSs. Indomethacin impaired mitochondrial dynamics by promoting fissogenic activation and mitochondrial recruitment of DRP1 and down-regulating fusogenic optic atrophy 1 (OPA1) and mitofusins in rat gastric mucosa. Consistent with OPA1 maintaining cristae architecture, its down-regulation resulted in EM-detectable cristae deformity. Deregulated mitochondrial dynamics resulting in defective mitochondria were evident from enhanced Parkin expression and mitochondrial proteome ubiquitination. Indomethacin ultimately induced mitochondrial metabolic and bioenergetic crises in the rat stomach, indicated by compromised fatty acid oxidation, reduced complex I- associated electron transport chain activity, and ATP depletion. Interestingly, Mdivi-1, a fission-preventing mito-protective drug, reversed indomethacin-induced DRP1 phosphorylation on Ser-616, mitochondrial proteome ubiquitination, and mitochondrial metabolic crisis. Mdivi-1 also prevented indomethacin-induced mitochondrial macromolecular damage, caspase activation, mucosal inflammation, and gastric mucosal injury. Our results identify mitochondrial hyper-fission as a critical and common subcellular event triggered by indomethacin that promotes apoptosis in both gastric cancer and normal mucosal cells, thereby contributing to mucosal injury.
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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.