Open AccessTrans ‐3,5,4´‐trimethoxystilbene reduced gefitinib resistance in NSCLC s via suppressing MAPK /Akt/Bcl‐2 pathway by upregulation of miR‐345 and miR‐498
Author(s) -
Lu Min,
Liu Bin,
Xiong Hui,
Wu Fang,
Hu Chunhong,
Liu Ping
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14086
Subject(s) - gefitinib , mapk/erk pathway , cancer research , downregulation and upregulation , protein kinase b , apoptosis , epidermal growth factor receptor , mtt assay , chemistry , flow cytometry , cell growth , lung cancer , cell cycle , signal transduction , biology , medicine , microbiology and biotechnology , oncology , receptor , gene , biochemistry
Abstract Despite initial dramatic efficacy of epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors ( EGFR ‐ TKI s) in EGFR ‐mutant lung cancer patients, subsequent emergence of acquired resistance is almost inevitable. Resveratrol and its derivatives have been found to exert some effects on EGFR ‐ TKI resistance in non‐small cell lung cancer ( NSCLC ), but the underlying mechanisms remain unclear. We screened several NSCLC cell lines with gefitinib resistance by MTT assay and analysed the miR‐345/miR‐498 expression levels. NSCLC cells were pre‐treated with a resveratrol derivative, trans ‐3,5,4‐trimethoxystilbene ( TMS ) and subsequently challenged with gefitinib treatment. The changes in apoptosis and miR‐345/miR‐498 expression were analysed by flow cytometry and q‐ PCR respectively. The functions of miR‐345/miR‐498 were verified by CCK ‐8 assay, cell cycle analysis, dual‐luciferase reporter gene assay and immunoblotting analysis. Our results showed that the expression of miR‐345 and miR‐498 significantly decreased in gefitinib resistant NSCLC cells. TMS pre‐treatment significantly upregulated the expression of miR‐345 and miR‐498 increasing the sensitivity of NSCLC cells to gefitinib and inducing apoptosis. MiR‐345 and miR‐498 were verified to inhibit proliferation by cell cycle arrest and regulate the MAPK /c‐Fos and AKT /Bcl‐2 signalling pathways by directly targeting MAPK 1 and PIK 3R1 respectively. The combination of TMS and gefitinib promoted apoptosis also by miR‐345 and miR‐498 targeting the MAPK /c‐Fos and AKT /Bcl‐2 signalling pathways. Our study demonstrated that TMS reduced gefitinib resistance in NSCLC s via suppression of the MAPK /Akt/Bcl‐2 pathway by upregulation of miR‐345/498. These findings would lay the theoretical basis for the future study of TMS for the treatment of EGFR ‐ TKI resistance in NSCLC s.