Shenqifuzheng injection inhibits lactic acid-induced cisplatin resistance in NSCLC by affecting FBXO22/p53 axis through FOXO3.

IF 5.8 2区医学 Q1 Medicine Respiratory Research Pub Date : 2024-11-01 DOI:10.1186/s12931-024-03013-8

Wei Bo, Xiaokai Wang, Ning Yu, Chun Wang, Chunying Liu

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引用次数: 0

Abstract

Background: Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers. Cisplatin (DDP)-based combination chemotherapy is the main treatment of NSCLC. Due to resistance to DDP, 5-year overall survival rate of NSCLC patients is very low. Shenqifuzheng injection (SQFZ) is essential for lung cancer progression. However, whether SQFZ plays a role in DDP resistance in NSCLC and its molecular mechanism remains unclear.

Methods: Levels of FOXO3, FBXO22 and p53 in NSCLC tissues and cells were assessed by RT-qPCR and Western blot. Cell proliferation and apoptosis were analyzed utilizing CCK-8, Colony formation and Flow cytometry assays. Lactate (LA) levels were tested via ELISA. ChIP and Dual luciferase reporter assays validated regulatory relationship between FOXO3 and FBXO22. Immunoprecipitation assay evaluated p53 ubiquitination levels. The subcutaneous tumor model of nude mice was constructed. TUNEL staining detected apoptosis in tissues, and IHC assessed expression of Ki67, FOXO3, FBXO22 and p53.

Results: FOXO3 was decreased, whereas LA and FBXO22 were increased in NSCLC patients. LA led to a higher DDP resistance in A549/DDP cells, while SQFZ reversed this effect by upregulating FOXO3. Furthermore, FBXO22 was a downstream effecter of FOXO3 and FBXO22 affected p53 ubiquitination to reverse the inhibitory effect of SQFZ. We next found SQFZ inhibited LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 axis. Finally, SQFZ regulated LA-mediated DDP resistance in NSCLC nude mice.

Conclusion: SQFZ influences LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 pathway, providing a promising agent for NSCLC treatment.

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参芪扶正注射液通过FOXO3影响FBXO22/p53轴，抑制乳酸诱导的NSCLC顺铂耐药。

背景：非小细胞肺癌（NSCLC）占肺癌的 80%：非小细胞肺癌（NSCLC）占肺癌的 80%。以顺铂（DDP）为基础的联合化疗是治疗 NSCLC 的主要方法。由于对DDP产生耐药性，NSCLC患者的5年总生存率非常低。神曲扶正注射液（SQFZ）对肺癌的进展至关重要。然而，SQFZ是否在NSCLC的DDP耐药性中发挥作用及其分子机制仍不清楚：方法：通过RT-qPCR和Western blot评估NSCLC组织和细胞中FOXO3、FBXO22和p53的水平。利用 CCK-8、集落形成和流式细胞术分析细胞增殖和凋亡。通过 ELISA 检测乳酸（LA）水平。ChIP 和双荧光素酶报告实验验证了 FOXO3 和 FBXO22 之间的调控关系。免疫沉淀测定评估了 p53 泛素化水平。构建了裸鼠皮下肿瘤模型。TUNEL染色检测组织凋亡，IHC评估Ki67、FOXO3、FBXO22和p53的表达：结果：在NSCLC患者中，FOXO3减少，而LA和FBXO22增加。LA导致A549/DDP细胞对DDP的抗性增强，而SQFZ通过上调FOXO3逆转了这种效应。此外，FBXO22是FOXO3的下游效应器，FBXO22影响了p53的泛素化，从而逆转了SQFZ的抑制作用。接下来，我们发现SQFZ通过FOXO3/FBXO22/p53轴抑制LA诱导的NSCLC的DDP耐药性。最后，SQFZ调节了NSCLC裸鼠对LA介导的DDP耐药性：结论：SQFZ通过FOXO3/FBXO22/p53途径影响LA诱导的NSCLC DDP耐药性，为NSCLC治疗提供了一种有前景的药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Respiratory Research RESPIRATORY SYSTEM-

CiteScore

9.70

自引率

1.70%

发文量

314

审稿时长

4-8 weeks

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.