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

摘要

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as first-line recommended therapy for EGFR mutant non-small cell lung cancer patients. However, epithelial-mesenchymal transition (EMT) can reduce EGFR-TKI sensitivity and lead to resistance. This study was designed to investigate the reversal effect of astragalus polysaccharides (APS) on gefitinib resistance (GR) and to elucidate the underlying mechanisms. PC9 and HCC827 lung cancer cells were stimulated by TGF-β1 to develop EMT-associated GR cells. Cell proliferation, migration and apoptosis assays were used to confirm the effect of gefitinib on GR cells and the therapeutic effect of APS on GR cells after knockdown and over-expression of related signaling pathways. Reverse transcription polymerase chain reaction, western blotting, and immunofluorescent staining assays were used to evaluate the expression levels of E-cadherin, N-cadherin, vimentin, PD-L1, and SREBP-1. Furthermore, proliferation and migration abilities were enhanced, while apoptosis ability was weakened in EMT-associated GR cells. After over-expression of PD-L1, expression levels of N-cadherin, vimentin and SREBP-1 increased, while expression of E-cadherin decreased. After knockdown of PD-L1 or SREBP-1, E-cadherin expression increased, while expression of N-cadherin and vimentin decreased. Further studies revealed that APS promoted apoptosis and reduced proliferation and migration abilities in GR cells. Moreover, APS increased expression of E-cadherin and decreased expression of N-cadherin and vimentin, indicating that it may be related to inhibition of the PD-L1/SREBP-1/EMT signaling pathway. Based on these findings, it can be concluded that APS can reverse acquired resistance to gefitinib in lung cancer cells by inhibiting the PD-L1/SREBP-1/EMT signaling pathway.