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Proteomic study on nintedanib in gastric cancer cells
Xiaohua Dong1,2,3, Liuli Wang1, Da Wang2
1The First School of Clinical Medicine, Lanzhou University, LanZhou, China.
Background:
Gastric cancer is a very common gastrointestinal tumor with a high mortality rate. Nintedanib has been shown to significantly reduce tumor cell proliferation and increase apoptosis in gastric cancer cells in vitro. However, its systemic action mechanism on gastric cancer cells remains unclear. A high-throughput proteomic approach should help identify the potential mechanisms and targets of nintedanib on gastric cancer cells.
Methods:
The effects of nintedanib on the biological behavior of gastric cancer cells were evaluated. A cytotoxic proliferation assay was performed to estimate the half maximal inhibitory concentration (IC50). AGS cells were divided into control, and nintedanib-treated groups (5 µM, 48 h), and differential protein expression was investigated using tandem mass tags (TMT) proteomics. The molecular mechanisms of these differentially expressed proteins and their network interactions were then analyzed using bioinformatics, and potential nintedanib targets were identified.
Results:
This study identified 845 differentially expressed proteins in the nintedanib-treated group (compared to the control group), comprising 526 up-regulated and 319 down-regulated proteins. Bioinformatics analysis revealed that the differentially expressed proteins were primarily enriched in biological pathways for branched-chain amino acid metabolism, steroid biosynthesis, propionate metabolism, fatty acid metabolism, lysosome, peroxisome, and ferroptosis. Key driver analysis revealed that proteins, such as enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), isocitrate dehydrogenase 1 (IDH1), acyl-CoA oxidase 1 (ACOX1), acyl-CoA oxidase 2 (ACOX2), acyl-CoA oxidase 3 (ACOX3), and acetyl-CoA acyltransferase 1 (ACAA1) could be linked with nintedanib action.
Conclusion:
Nintedanib inhibits the proliferation, invasion, and metastasis of gastric cancer cells. The crossover pathways and protein networks predicted by proteomics should provide more detailed molecular information enabling the use of nintedanib against gastric cancer.
Insights
Nintedanib reduces gastric cancer cell growth by altering key metabolic pathways. Proteomics identified specific proteins involved in these changes, offering new therapeutic targets for gastric cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Gastric cancer is a prevalent malignancy with high mortality.
- Nintedanib demonstrates anti-proliferative and pro-apoptotic effects on gastric cancer cells in vitro.
- The systemic mechanism of nintedanib in gastric cancer remains incompletely understood.
Purpose of the Study:
- To elucidate the systemic mechanism of action of nintedanib in gastric cancer cells.
- To identify potential molecular targets and pathways affected by nintedanib treatment.
- To utilize high-throughput proteomics for comprehensive analysis.
Main Methods:
- Gastric cancer cells (AGS) were treated with nintedanib (5 µM, 48 h).
- Cytotoxic proliferation assays determined the IC50.
- Tandem mass tags (TMT) proteomics analyzed differential protein expression.
- Bioinformatics tools were employed for pathway and network analysis.
Main Results:
- 845 differentially expressed proteins were identified (526 upregulated, 319 downregulated).
- Enrichment analysis highlighted pathways in amino acid and lipid metabolism, lysosome, peroxisome, and ferroptosis.
- Key proteins linked to nintedanib action include EHHADH, IDH1, ACOX1-3, and ACAA1.
Conclusions:
- Nintedanib effectively inhibits gastric cancer cell proliferation, invasion, and metastasis.
- Proteomic analysis reveals critical molecular pathways and protein networks influenced by nintedanib.
- These findings provide a deeper understanding for nintedanib's application in gastric cancer therapy.
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