去甲斑蝥素抑制METTL16/MAT2A通路诱导卵巢癌细胞凋亡并抑制肿瘤进展

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics Pub Date : 2025-06-13 DOI:10.1016/j.abb.2025.110510

Yuan-Yuan Zhang , Qiu-Xia Zeng , Li Wang , Kong-Xian Li , Shun Zhang , Ping Wan , Xue-Ming Zhou , Qi Chen

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引用次数: 0

摘要

目的：研究去甲斑马素（NCTD）在卵巢癌中的抗肿瘤作用，阐明其分子靶点和作用机制，重点研究甲基转移酶样蛋白16 (METTL16)/蛋氨酸腺苷转移酶ⅱα (MAT2A)信号轴。材料和方法：采用免疫组织化学、实时定量聚合酶链反应和western blotting分析卵巢癌组织和细胞中METTL16和MAT2A的表达水平。培养人卵巢癌细胞系ES2和SKOV3，通过基因重组使METTL16过表达。使用细胞计数试剂盒-8测定不同浓度的NCTD的细胞毒性作用。通过流式细胞术和伤口愈合（划痕）试验评估细胞凋亡、增殖和迁移。建立人卵巢癌皮下移植瘤裸鼠模型，观察其体内抗肿瘤效果。采用酶联免疫吸附法定量细胞内s -腺苷蛋氨酸（SAM）水平。结果：METTL16和MAT2A基因在卵巢癌组织和细胞系中的表达水平显著升高（p < 0.05）。10 μg/mL NCTD可显著抑制ES2和SKOV3细胞的增殖，诱导细胞凋亡。NCTD还能抑制细胞迁移和血管生成活性，下调相关基因的表达，而过表达METTL16会减弱这种作用（p < 0.05）。在异种移植瘤模型中，NCTD显著降低肿瘤体积，下调METTL16、MAT2A、蛋白磷酸酶2A （PP2A）和血管内皮生长因子的表达（p < 0.05）。结论：NCTD通过降低细胞内s -腺苷蛋氨酸水平，促进PP2A去甲基化，抑制METTL16/MAT2A信号通路，在卵巢癌中发挥抗肿瘤作用。这些作用有助于细胞周期阻滞、增殖抑制和细胞凋亡增强，支持NCTD在卵巢恶性肿瘤中的治疗潜力。

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Norcantharidin inhibits the METTL16/MAT2A pathway to induce apoptosis and suppress tumor progression in ovarian cancer

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Norcantharidin inhibits the METTL16/MAT2A pathway to induce apoptosis and suppress tumor progression in ovarian cancer

Objective

This study aimed to investigate the antitumor effects of norcantharidin (NCTD) in ovarian cancer and to elucidate its molecular targets and mechanisms of action, with a focus on the methyltransferase-like protein 16 (METTL16)/methionine adenosyl transferase II alpha (MAT2A) signaling axis.

Materials and methods

Expression levels of METTL16 and MAT2A were analyzed in ovarian cancer tissues and cells using immunohistochemistry, quantitative real-time polymerase chain reaction, and western blotting. Human ovarian cancer cell lines (ES2 and SKOV3) were cultured and subjected to METTL16 overexpression via gene recombination. The cytotoxic effects of varying concentrations of NCTD were assessed using the Cell Counting Kit-8 assay. Apoptosis, proliferation, and migration were evaluated through flow cytometry and wound healing (scratch) assays. A subcutaneous xenograft model of human ovarian cancer was established in nude mice to assess in vivo antitumor efficacy. Enzyme-linked immunosorbent assay was used to quantify intracellular levels of S-adenosylmethionine (SAM).

Results

METTL16 and MAT2A gene expression levels were significantly elevated in ovarian cancer tissues and cell lines (p < 0.05). Treatment with NCTD at 10 μg/mL significantly inhibited proliferation and induced apoptosis in ES2 and SKOV3 cells. NCTD also suppressed cellular migration and angiogenic activity, with downregulation of related gene expression, effects that were attenuated by METTL16 overexpression (p < 0.05). In the xenograft model, NCTD administration significantly reduced tumor volume and downregulated expression of METTL16, MAT2A, protein phosphatase 2A (PP2A), and vascular endothelial growth factor (p < 0.05).

Conclusions

NCTD exerts antineoplastic effects in ovarian cancer by reducing intracellular S-adenosylmethionine levels, promoting PP2A demethylation, and inhibiting the METTL16/MAT2A signaling pathway. These effects contribute to cell cycle arrest, suppressed proliferation, and enhanced apoptosis, supporting the therapeutic potential of NCTD in ovarian malignancies.

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来源期刊

Archives of biochemistry and biophysics 生物-生化与分子生物学

CiteScore

7.40

自引率

0.00%

发文量

245

审稿时长

26 days

期刊介绍： Archives of Biochemistry and Biophysics publishes quality original articles and reviews in the developing areas of biochemistry and biophysics. Research Areas Include: • Enzyme and protein structure, function, regulation. Folding, turnover, and post-translational processing • Biological oxidations, free radical reactions, redox signaling, oxygenases, P450 reactions • Signal transduction, receptors, membrane transport, intracellular signals. Cellular and integrated metabolism.