下调GFPT2通过调节己糖胺生物合成途径，抑制肿瘤生长，增强STK11/KRAS突变型非小细胞肺癌顺铂化疗敏感性

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine Pub Date : 2025-04-19 DOI:10.1016/j.cyto.2025.156943

Cheng Zhang , Xuelei Yin , Jun Jiang , Peng Wang , Yirong Wang

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引用次数: 0

摘要

目的探讨GFPT2在STK11/KRAS肺癌细胞对顺铂化疗敏感性中的作用及其机制。材料,方法利用sa549和H460细胞分析GFPT2对顺铂化疗敏感性的影响，两者均携带KRAS突变，H460细胞存在LKB1失活突变，符合KRAS/LKB1共突变肿瘤模型的要求。同时测定HBP通路中UDP-GlcNAc、OGT、OGA和O-GlcNAc的水平。为了验证HBP的潜在作用，我们添加了OGT抑制剂。在体内，我们构建了携带A549肿瘤的裸鼠模型，进一步验证体外细胞实验的结果。结果gfpt2沉默可显著抑制细胞增殖、侵袭和迁移，促进细胞凋亡，增强顺铂的治疗效果(p <；0.05)。经过OSMI-1加工后，GFPT2通过ogt介导的HBP增强O-GlcNAc修饰水平，从而降低STK11/KRAS突变细胞对顺铂化疗的敏感性。此外，GFPT2沉默可增强顺铂化疗敏感性，抑制肿瘤生长，而过表达GFPT2可减弱这一作用(p <；0.05)。以上结果为KRAS/LKB1突变型肺癌的临床治疗提供了新的靶点和联合治疗方案。结论本研究发现抑制GFPT2可通过OGT介导的HBP通路增强顺铂对STK11/KRAS/LKB1突变型nsclc细胞的化疗敏感性，填补了KRAS/LKB1突变型肺癌化疗耐药机制的关键空白。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Downregulation of GFPT2 enhances cisplatin chemotherapy sensitivity in STK11/KRAS mutant non-small cell lung cancer by regulating the hexosamine biosynthesis pathway, resisting tumor growth

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Downregulation of GFPT2 enhances cisplatin chemotherapy sensitivity in STK11/KRAS mutant non-small cell lung cancer by regulating the hexosamine biosynthesis pathway, resisting tumor growth

Objective

To explore the role of GFPT2 in the sensitivity of STK11/KRAS lung cancer cells to cisplatin chemotherapy, and its underlying mechanism.

Materials & methods

A549 and H460 cells were used to analyze the effect of GFPT2 on cisplatin chemotherapy sensitivity, as both carry KRAS mutations and H460 has LKB1 inactivation mutations, meeting the requirements of a KRAS/LKB1 co mutant tumor model. The levels of UDP-GlcNAc, OGT, OGA, and O-GlcNAc in the HBP pathway were also determined. To verify the potential role of HBP, we added OGT inhibitors. In vivo, we constructed a nude mouse model bearing A549 tumor to further validate the results of in vitro cell experiments.

Results

GFPT2 silencing can significantly inhibit cell proliferation, invasion, and migration, promote cell apoptosis, and enhance the effect of cisplatin (p < 0.05). After OSMI-1 processing, GFPT2 enhances O-GlcNAc modification levels via the OGT-mediated HBP, thereby decreasing the sensitivity of STK11/KRAS mutant cells to cisplatin chemotherapy. In addition, GFPT2 silencing enhances the chemotherapy sensitivity of cisplatin and inhibits tumor growth, while overexpression of GFPT2 weakens this effect (p < 0.05). The above results provide new targets and combination therapy options for the clinical treatment of KRAS/LKB1 mutant lung cancer.

Conclusion

Our study found that inhibiting GFPT2 can enhance the chemotherapy sensitivity of cisplatin to STK11/KRAS/LKB1 mutant NSCLCs cells through the OGT mediated HBP pathway, filling a key gap in the chemotherapy resistance mechanism of KRAS/LKB1 mutant lung cancer.

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来源期刊

Cytokine 医学-免疫学

CiteScore

7.60

自引率

2.60%

发文量

262

审稿时长

48 days

期刊介绍： The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. * Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors. We will publish 3 major types of manuscripts: 1) Original manuscripts describing research results. 2) Basic and clinical reviews describing cytokine actions and regulation. 3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.