Astragalus polysaccharides reverse gefitinib resistance by inhibiting mesenchymal transformation in lung adenocarcinoma cells

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are first-line treatments for EGFR-mutant non-small cell lung cancer (NSCLC).
• Epithelial-mesenchymal transition (EMT) is a key mechanism leading to reduced sensitivity and resistance to EGFR-TKIs.

Purpose of the Study:

• To investigate the efficacy of astragalus polysaccharides (APS) in reversing gefitinib resistance (GR) in NSCLC.
• To elucidate the underlying molecular mechanisms by which APS affects GR, focusing on the PD-L1/SREBP-1/EMT signaling pathway.

Main Methods:

• Induction of EMT-associated GR in PC9 and HCC827 lung cancer cells using TGF-β1.
• Assessment of cell proliferation, migration, and apoptosis using various assays.
• Evaluation of gene and protein expression levels (E-cadherin, N-cadherin, vimentin, PD-L1, SREBP-1) via RT-PCR, Western blotting, and immunofluorescence.
• Manipulation of signaling pathways through knockdown and overexpression techniques.

Main Results:

• EMT-associated GR cells exhibited enhanced proliferation and migration, with decreased apoptosis.
• Overexpression of PD-L1 upregulated N-cadherin, vimentin, and SREBP-1 while downregulating E-cadherin.
• Knockdown of PD-L1 or SREBP-1 increased E-cadherin and decreased N-cadherin and vimentin expression.
• APS treatment promoted apoptosis and reduced proliferation and migration in GR cells.
• APS increased E-cadherin and decreased N-cadherin and vimentin, suggesting inhibition of the PD-L1/SREBP-1/EMT pathway.

Conclusions:

• Astragalus polysaccharides (APS) demonstrate a significant effect in reversing acquired gefitinib resistance in lung cancer cells.
• APS exerts its therapeutic effect by inhibiting the PD-L1/SREBP-1/EMT signaling pathway, restoring sensitivity to gefitinib.
• These findings highlight APS as a potential therapeutic agent to overcome EGFR-TKI resistance in non-small cell lung cancer.