RRC ID 51659
Author Kurimoto R, Iwasawa S, Ebata T, Ishiwata T, Sekine I, Tada Y, Tatsumi K, Koide S, Iwama A, Takiguchi Y.
Title Drug resistance originating from a TGF-β/FGF-2-driven epithelial-to-mesenchymal transition and its reversion in human lung adenocarcinoma cell lines harboring an EGFR mutation.
Journal Int J Oncol
Abstract Epithelial-to-mesenchymal transition (EMT) is a malignant cancer phenotype characterized by augmented invasion and metastasis, chemoresistance, and escape from host-immunity. This study sought to identify efficient methods for inducing EMT reversion, to evaluate alterations in chemosensitivity and immune-protectiveness, and to elucidate the underlying mechanisms. In this study, the human lung adenocarcinoma cell lines PC-9 and HCC-827, harboring an EGFR mutation, were treated with TGF-β and FGF-2 to induce EMT. The phenotypic alterations were evaluated by RT-PCR, fluorescent immunohistochemistry, cell-mobility, and flow cytometry. Chemosensitivity to gefitinib and cisplatin was evaluated using an MTT assay and apoptosis. Immune-protectiveness was evaluated by PD-L1 expression. A combination of TGF-β and FGF-2 efficiently induced EMT in both cell lines: through Smad3 pathway in PC-9, and through Smad3, MEK/Erk, and mTOR pathways in HCC-827. The mTOR inhibitor PP242, metformin, and DMSO reverted EMT to different extent and through different pathways, depending on the cell lines. EMT induction reduced the sensitivity to gefitinib in both cell lines and to cisplatin in HCC-827, and it increased PD-L1 expression in both cell lines. EMT reversion using each of the 3 agents partly restored chemosensitivity and suppressed PD-L1 expression. Thus, chemoresistance and increased PD-L1 expression caused by EMT can be successfully reverted by EMT-reverting agents.
Volume 48(5)
Pages 1825-36
Published 2016-5-1
DOI 10.3892/ijo.2016.3419
PMID 26984042
PMC PMC4809654
MeSH Adenocarcinoma / genetics* Adenocarcinoma / metabolism Adenocarcinoma of Lung Antineoplastic Agents / pharmacology B7-H1 Antigen / metabolism Cell Line, Tumor Cell Survival / drug effects Cisplatin / pharmacology Dimethyl Sulfoxide / pharmacology* Drug Resistance, Neoplasm / drug effects* Epithelial-Mesenchymal Transition ErbB Receptors / genetics* Fibroblast Growth Factor 2 / pharmacology Gefitinib Gene Expression Regulation, Neoplastic / drug effects Humans Indoles / pharmacology* Lung Neoplasms / genetics* Lung Neoplasms / metabolism Metformin / pharmacology* Mutation Purines / pharmacology* Quinazolines / pharmacology Transforming Growth Factor beta / pharmacology
IF 3.899
Times Cited 30
Human and Animal Cells PC-9(RCB4455)