RRC ID 51585
著者 Sakamoto T, Kobayashi S, Yamada D, Nagano H, Tomokuni A, Tomimaru Y, Noda T, Gotoh K, Asaoka T, Wada H, Kawamoto K, Marubashi S, Eguchi H, Doki Y, Mori M.
タイトル A Histone Deacetylase Inhibitor Suppresses Epithelial-Mesenchymal Transition and Attenuates Chemoresistance in Biliary Tract Cancer.
ジャーナル PLoS One
Abstract Epithelial-mesenchymal transition (EMT) is involved in the characteristics of malignancy, such as invasion, metastasis, and chemoresistance. In biliary tract cancer (BTC), EMT is induced by transforming growth factor-beta 1 (TGF-β1). The EMT is reversible; therefore, it is conceivable that it could be related to some epigenetic changes. We focused on histone deacetylase (HDAC) inhibitors as regulators of TGF-β1 signaling, and investigated their effect on EMT and chemoresistance. We employed four BTC cell lines (MzChA-1, gemcitabine-resistant MzChA-1, TFK-1, and gemcitabine-resistant TFK-1) and used vorinostat as the HDAC inhibitor. The relative mRNA expression of an epithelial marker (CDH1) and mesenchymal markers (CDH2, vimentin, SNAI1) were measured by qRT-PCR to evaluate factors associated with EMT. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to evaluate the chemoresistance of each cell line. In addition, NOD/SCID mice were used to evaluate the effect of vorinostat in vivo. In the parent MzChA-1 and TFK-1 cell lines, TGF-β1 induced EMT and chemoresistance; while vorinostat inhibited the EMT and chemoresistance induced by TGF-β1. In gemcitabine-resistant cell lines that highly expressed TGF-β1, vorinostat inhibited EMT and attenuated chemoresistance. We showed that vorinostat inhibits nuclear translocation of SMAD4 which is a signaling factor of TGF-β1, and this is one of the mechanisms by which vorinostat regulates EMT. We also showed that vorinostat attenuates the binding affinity of SMAD4 to the CDH1-related transcription factors SNAI1, SNAI2, ZEB1, ZEB2, and TWIST. Furthermore, combination therapy with vorinostat and gemcitabine improved survival time in the mice xenografted with gemcitabine resistant MzChA-1 cells. In conclusion, vorinostat regulated TGF-β1-induced EMT and chemoresistance through inhibition of SMAD4 nuclear translocation.
巻・号 11(1)
ページ e0145985
公開日 2016-1-1
DOI 10.1371/journal.pone.0145985
PII PONE-D-15-26531
PMID 26726879
PMC PMC4699768
MeSH Animals Antineoplastic Agents / therapeutic use* Biliary Tract Neoplasms / drug therapy* Biliary Tract Neoplasms / pathology Cell Line, Tumor Drug Resistance, Neoplasm* Epithelial-Mesenchymal Transition / drug effects* Histone Deacetylase Inhibitors / pharmacology* Humans Mice Transforming Growth Factor beta1 / physiology Xenograft Model Antitumor Assays
IF 2.74
引用数 33
リソース情報
ヒト・動物細胞 TFK-1(RCB2537)