Mechanistic Insights into Luteolin’s Effect on Gastric Cancer: Inhibition of MCL1 and Its Impact on PI3K-Akt and JAK-STAT Signaling
Year: 2025
Type: article
Abstract: Objective: This study investigates the molecular mechanisms by which luteolin (Lu) regulates the PI3K-Akt and JAK-STAT signaling pathways through MCL1, thereby influencing chemotherapy resistance in gastric cancer (GC) cells. Materials and Methods: Network pharmacology was employed to identify target genes of Lu and GC-related targets from multiple databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Quantitative reverse transcription-polymerase chain reaction was performed to quantify the expression of MCL1, resistance-related genes (GST-π, Topo-II, MRP), and apoptosis-related genes (caspase-3, Bax/Bcl-2). Western blot analysis was used to assess protein levels of MCL1, p-p70S6/p70S6, p-AKT/AKT, JAK, and p-STAT3/STAT3. Cell proliferation, invasion, migration, and apoptosis were evaluated using the cell counting kit-8 (CCK-8), Transwell, scratch assay, and flow cytometry, respectively. Xenograft tumor experiments in nude mice were conducted to assess in vivo tumor formation. Results: A total of 50 target genes of Lu and 134 GC-related targets were identified. Protein–protein interaction network analysis revealed nine key target genes. GO and KEGG analyses indicated that MCL1 plays a role in regulating the JAK-STAT and PI3K-Akt pathways in GC cells. Lu inhibited cell proliferation, invasion, migration, and chemotherapy resistance while promoting apoptosis in GC cells. Furthermore, Lu-mediated downregulation of MCL1 suppressed the JAK-STAT and PI3K-Akt pathways, reversing proliferation, invasion, migration, and chemotherapy resistance while enhancing apoptosis. Conclusions: Lu may inhibit the JAK-STAT and PI3K-Akt pathways by downregulating MCL1, thereby reducing proliferation, invasion, migration, and chemotherapy resistance in GC cells.
Authors: Xiao-Fei Zhang, Miao-Miao Zhang, Peng-Zhan Yan, Xiao-Nan Shi, Ya-Qing Li, Bin Jia
Institution: First Affiliated Hospital of Zhengzhou University
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7082375084