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Drug resistance originating from a TGF-?/FGF-2-driven epithelial-to-mesenchymal
transition and its reversion in human lung adenocarcinoma cell lines harboring an
EGFR mutation
#MMPMID26984042
Kurimoto R
; Iwasawa S
; Ebata T
; Ishiwata T
; Sekine I
; Tada Y
; Tatsumi K
; Koide S
; Iwama A
; Takiguchi Y
Int J Oncol
2016[May]; 48
(5
): 1825-36
PMID26984042
show ga
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-? 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-? 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.
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