Ketamine Induces Mitochondrial Fission and Dysfunction in Cervical Cancer Cells via RhoA-Dependent DRP-1 Activation

IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yanfang Zhou, Guangming Chen, Ye Zhu
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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.

Abstract Image

氯胺酮通过rhoa依赖性DRP-1激活诱导宫颈癌细胞线粒体分裂和功能障碍
线粒体断裂与线粒体功能障碍密切相关,已成为宫颈癌的关键治疗靶点。氯胺酮是一种众所周知的麻醉剂,通过诱导细胞毒性、损害线粒体功能和促进肿瘤细胞凋亡,在癌症治疗中显示出潜力。值得注意的是,氯胺酮在线粒体网络动力学中的调节作用在当前的科学文献中仍未被探索。在这项研究中,我们证明氯胺酮对C33A宫颈癌细胞具有显著的细胞毒性作用,这可以通过γ-谷氨酰转肽酶(GGT)水平和乳酸脱氢酶(LDH)释放的剂量依赖性增加来证明,同时伴随着细胞活力的相应降低。在100 μM下,氯胺酮诱导线粒体功能障碍,其特征是复合物IV活性、线粒体膜电位(MMP)和ATP生成降低,以及线粒体断裂。在机制上,氯胺酮上调线粒体p-Drp1水平,但不改变总DRP-1,并增强CaMK II和RhoA的表达,但不影响Rac1/Cdc42。抑制RhoA,而不是CaMK II,可以减弱氯胺酮诱导的线粒体DRP-1激活、断裂和功能障碍,这表明RhoA是一个关键的介质。这些发现突出了氯胺酮作为一种靶向宫颈癌线粒体动力学的治疗剂的潜力。
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来源期刊
CiteScore
5.80
自引率
2.80%
发文量
277
审稿时长
6-12 weeks
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.
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