Valproic acid inhibits irradiation-induced epithelial-mesenchymal transition and stem cell-like characteristics in esophageal squamous cell carcinoma

Abstract

Esophageal carcinoma is one of the most aggressive malignancies, and is characterized by poor response to current therapy and a dismal survival rate. In this study we investigated whether irradiation induces epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) TE9 cells and whether the classic histone deacetylase (HDAC) inhibitor valproic acid (VPA) suppresses these changes. First, we showed that 2 Gy irradiation induced spindle cell-like morphologic changes, decreased expression of membranous E-cadherin, upregulated vimentin expression, and altered the localization of β-catenin from its usual membrane-bound location to cytoplasm in TE9 cells. Irradiation induced upregulation of transcription factors including Slug, Snail, and Twist, which regulate EMT. Stimulation by irradiation resulted in increased TGF-β1 and HIF-1α expression and induced Smad2 and Smad3 phosphorylation. Furthermore, irradiation enhanced CD44 expression, indicating acquisition of cancer stem-like cell properties. In addition, irradiation enhanced invasion and migration ability with upregulation of matrix metalloproteinases. These findings indicate that single-dose irradiation can induce EMT in ESCC cells. Second, we found that treatment with 1 mM VPA induced reversal of EMT caused by irradiation in TE9 cells, resulting in attenuated cell invasion and migration abilities. These results suggest that VPA might have clinical value to suppress irradiation-induced EMT. The reversal of EMT by HDAC inhibitors may be a new therapeutic strategy to improve the effectiveness of radiotherapy in ESCC by inhibiting the enhancement of invasion and metastasis.

Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

“…However, the role of VPA in the regulation of the EMT can be both positive and negative. For example, EMT is reversed by VPA by inhibiting the enhancement of invasion and metastasis in esophageal squamous cell carcinoma . VPA was also shown to enhance the EMT process via transcriptional and post‐transcriptional up‐regulation of Snail in hepatocarcinoma cells .…”

Epithelial plasticity and cancer stem cells: Major mechanisms of cancer pathogenesis and therapy resistance

“…Clinical value of valproic acid (VPA), histone deacetylase (HDAC) inhibitor has been investigated to suppress irradiation-induced EMT, attenuate cell invasion, migration abilities and improve the effectiveness of radiotherapy in the treatment of esophageal squamous cell carcinoma (ESCC) TE9 cells[ 34 ]. Angiopoietin-like protein 1 (ANGPTL1) has been examined to reduce EMT-driven sorafenib resistance and cancer stemness properties of hepatocellular carcinoma cells through the inactivation of MET-extracellular receptor kinase/protein kinase B- dependent early growth response protein 1-Slug (MET receptor-AKT/ERK-Egr-1-Slug) signaling cascade[ 35 ].…”

Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way

“…Vimentin is an intermediate filament protein that is widely expressed in mesenchymal cells or tissues in the primitive streak during embryonic development, or in adults. In addition, various stimuli can induce cancer cells to express greater amounts of vimentin, which has been shown to serve a key role in the loss of cell adhesion and the acquisition of various abilities by cells, including migration, invasion, survival and signal transduction ( 13 – 15 ). When cancer cells experience EMT, along with overexpression of vimentin, properties associated with cancer progression are acquired.…”