Ergotamine Targets KIF5A to Facilitate Anoikis in Lung Adenocarcinoma

IF 1.9 4区医学 Q3 RESPIRATORY SYSTEM Clinical Respiratory Journal Pub Date : 2024-11-08 DOI:10.1111/crj.70020

Bin Bao, Xiaojun Yu, Wujun Zheng, Jiewei Sun

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Abstract

Background

Kinesin family member 5A (KIF5A) has been reported to be closely related to cancer progression. The aim of this study was to investigate the effect of KIF5A on lung adenocarcinoma (LUAD) and its potential molecular mechanisms.

Methods

Using bioinformatics analysis methods and molecular experiments, the expression of KIF5A in LUAD was analyzed, with its expression in attached and detached tumor cells assessed. Gene set enrichment analysis (GSEA) of KIF5A was carried out. The small molecular drug with the highest affinity for KIF5A was screened out through molecular docking experiments, which was validated through cellular thermal shift assay (CETSA). Quantitative polymerase chain reaction (qPCR) was employed to measure the expression levels of anoikis-repressing genes (BCL2, CAV1), as well as anoikis-inducing gene (PDCD4). CCK-8 assay was applied to examine cell viability. Cell colony formation experiments were utilized to evaluate cell proliferation ability.

Results

We observed that KIF5A was highly upregulated in LUAD tissues and cells, with a higher level detected in detached LUAD cells. By resorting to bioinformatics analysis, we discovered that KIF5A was abundant in the anoikis pathway. Knocking down KIF5A reinforced anoikis in LUAD. Further screening identified Ergotamine as the small molecular drug with the highest affinity for KIF5A. The CETSA confirmed the binding relationship between the two. In addition, Ergotamine has a promoting effect on the anoikis of LUAD, while overexpression of KIF5A reversed the effects of Ergotamine on LUAD cells.

Conclusion

This project uncovered that the small molecular drug Ergotamine targets and inhibits the expression of KIF5A. Downregulated KIF5A can enhance the anoikis of LUAD. Our results supported the inhibition of KIF5A as an attractive therapeutic strategy for LUAD. This finding provides a new innovative pathway for the treatment of LUAD and offers a strong theoretical basis for the development of therapeutic drugs targeting KIF5A.

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麦角胺以 KIF5A 为靶点促进肺腺癌的无丝分裂

背景：据报道，驱动蛋白家族成员 5A（KIF5A）与癌症进展密切相关。本研究旨在探讨 KIF5A 对肺腺癌（LUAD）的影响及其潜在的分子机制：方法：采用生物信息学分析方法和分子实验，分析了 KIF5A 在 LUAD 中的表达，评估了其在附着和脱落的肿瘤细胞中的表达。对KIF5A进行了基因组富集分析（GSEA）。通过分子对接实验筛选出与KIF5A亲和力最高的小分子药物，并通过细胞热转移试验（CETSA）进行验证。定量聚合酶链式反应（qPCR）用于检测抑制厌氧基因（BCL2、CAV1）和诱导厌氧基因（PDCD4）的表达水平。CCK-8 检测法用于检查细胞活力。细胞集落形成实验用于评估细胞增殖能力：结果：我们观察到 KIF5A 在 LUAD 组织和细胞中高度上调，在离体的 LUAD 细胞中检测到更高的水平。通过生物信息学分析，我们发现KIF5A在anoikis通路中含量丰富。敲除 KIF5A 会加强 LUAD 的厌氧作用。进一步筛选发现，麦角胺是与KIF5A亲和力最高的小分子药物。CETSA 证实了两者之间的结合关系。此外，麦角胺对LUAD的无丝分裂有促进作用，而KIF5A的过表达则逆转了麦角胺对LUAD细胞的影响：本项目发现小分子药物麦角胺能靶向抑制KIF5A的表达。结论：本项目发现小分子药物麦角胺能靶向抑制 KIF5A 的表达，而下调 KIF5A 能增强 LUAD 的厌氧反应。我们的研究结果支持将抑制 KIF5A 作为一种有吸引力的 LUAD 治疗策略。这一发现为治疗 LUAD 提供了一条新的创新途径，并为开发针对 KIF5A 的治疗药物提供了坚实的理论基础。

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来源期刊

Clinical Respiratory Journal 医学-呼吸系统

CiteScore

3.70

自引率

0.00%

发文量

104

审稿时长

>12 weeks

期刊介绍： Overview Effective with the 2016 volume, this journal will be published in an online-only format. Aims and Scope The Clinical Respiratory Journal (CRJ) provides a forum for clinical research in all areas of respiratory medicine from clinical lung disease to basic research relevant to the clinic. We publish original research, review articles, case studies, editorials and book reviews in all areas of clinical lung disease including: Asthma Allergy COPD Non-invasive ventilation Sleep related breathing disorders Interstitial lung diseases Lung cancer Clinical genetics Rhinitis Airway and lung infection Epidemiology Pediatrics CRJ provides a fast-track service for selected Phase II and Phase III trial studies. Keywords Clinical Respiratory Journal, respiratory, pulmonary, medicine, clinical, lung disease, Abstracting and Indexing Information Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Embase (Elsevier) Health & Medical Collection (ProQuest) Health Research Premium Collection (ProQuest) HEED: Health Economic Evaluations Database (Wiley-Blackwell) Hospital Premium Collection (ProQuest) Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) ProQuest Central (ProQuest) Science Citation Index Expanded (Clarivate Analytics) SCOPUS (Elsevier)