Ergotamine Targets KIF5A to Facilitate Anoikis in Lung Adenocarcinoma
Bin Bao1, Xiaojun Yu1, Wujun Zheng1
1Cardiothoracic Surgery Department, The First People's Hospital of Fuyang, Hangzhou, China.
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.
Insights
Kinesin family member 5A (KIF5A) is upregulated in lung adenocarcinoma (LUAD). Inhibiting KIF5A with Ergotamine enhances anoikis, offering a potential therapeutic strategy for LUAD treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Kinesin family member 5A (KIF5A) is implicated in cancer progression.
- Lung adenocarcinoma (LUAD) is a significant global health concern.
Purpose of the Study:
- To investigate the role of KIF5A in LUAD.
- To explore the molecular mechanisms underlying KIF5A's function in LUAD.
- To identify potential therapeutic targets for LUAD.
Main Methods:
- Bioinformatics analysis and molecular experiments were used to assess KIF5A expression in LUAD.
- Gene set enrichment analysis (GSEA) identified KIF5A's involvement in the anoikis pathway.
- Molecular docking and CETSA screened and validated Ergotamine as a KIF5A inhibitor.
Main Results:
- KIF5A was significantly upregulated in LUAD tissues and cells, particularly in detached cells.
- Knockdown of KIF5A promoted anoikis in LUAD cells.
- Ergotamine demonstrated high affinity for KIF5A, inhibiting its function and promoting LUAD cell anoikis.
Conclusions:
- Ergotamine targets and inhibits KIF5A expression in LUAD.
- Downregulation of KIF5A enhances anoikis, suggesting KIF5A inhibition as a therapeutic strategy for LUAD.
- This study provides a novel therapeutic avenue for LUAD treatment targeting KIF5A.
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