{"title":"Ketamine Induces Mitochondrial Fission and Dysfunction in Cervical Cancer Cells via RhoA-Dependent DRP-1 Activation","authors":"Yanfang Zhou, Guangming Chen, Ye Zhu","doi":"10.1002/jbt.70500","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Mitochondrial fragmentation, which is closely linked to mitochondrial dysfunction, has emerged as a critical treatment target for cervical cancer. Ketamine, a well-known anesthetic, has shown potential in cancer therapy by inducing cytotoxicity, impairing mitochondrial function, and promoting apoptosis in tumor cells. Notably, the regulatory role of ketamine in mitochondrial network dynamics remains unexplored in current scientific literature. In this study, we demonstrated that ketamine exerts significant cytotoxic effects on C33A cervical cancer cells, as evidenced by dose-dependent increases in γ-glutamyl transpeptidase (GGT) levels and lactate dehydrogenase (LDH) release, accompanied by a corresponding reduction in cell viability. At 100 μM, ketamine induces mitochondrial dysfunction, characterized by decreased Complex IV activity, mitochondrial membrane potential (MMP), and ATP production, along with mitochondrial fragmentation. Mechanistically, ketamine upregulates mitochondrial p-Drp1 levels without altering total DRP-1 and enhances the expression of CaMK II and RhoA, but not Rac1/Cdc42. Inhibition of RhoA, but not CaMK II, attenuates ketamine-induced mitochondrial DRP-1 activation, fragmentation, and dysfunction, suggesting that RhoA is a key mediator. These findings highlight ketamine's potential as a therapeutic agent targeting mitochondrial dynamics in cervical cancer.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 10","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biochemical and Molecular Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jbt.70500","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Mitochondrial fragmentation, which is closely linked to mitochondrial dysfunction, has emerged as a critical treatment target for cervical cancer. Ketamine, a well-known anesthetic, has shown potential in cancer therapy by inducing cytotoxicity, impairing mitochondrial function, and promoting apoptosis in tumor cells. Notably, the regulatory role of ketamine in mitochondrial network dynamics remains unexplored in current scientific literature. In this study, we demonstrated that ketamine exerts significant cytotoxic effects on C33A cervical cancer cells, as evidenced by dose-dependent increases in γ-glutamyl transpeptidase (GGT) levels and lactate dehydrogenase (LDH) release, accompanied by a corresponding reduction in cell viability. At 100 μM, ketamine induces mitochondrial dysfunction, characterized by decreased Complex IV activity, mitochondrial membrane potential (MMP), and ATP production, along with mitochondrial fragmentation. Mechanistically, ketamine upregulates mitochondrial p-Drp1 levels without altering total DRP-1 and enhances the expression of CaMK II and RhoA, but not Rac1/Cdc42. Inhibition of RhoA, but not CaMK II, attenuates ketamine-induced mitochondrial DRP-1 activation, fragmentation, and dysfunction, suggesting that RhoA is a key mediator. These findings highlight ketamine's potential as a therapeutic agent targeting mitochondrial dynamics in cervical cancer.
期刊介绍:
The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.