Abstract
Our previous studies have demonstrated that epidermal growth factor (EGF) can induce cell migration through the induction of cysteine-rich protein 61 (Cyr61) in human anaplastic thyroid cancer (ATC) cells. The aim of the present study was to determine the inhibitory effects of combined treatment with the peroxisome proliferator-activated receptor-γ (PPARγ) ligand troglitazone and the cholesterol-lowering drug lovastatin at clinically achievable concentrations on ATC cell migration. Combined treatment with 5 μM troglitazone and 1 μM lovastatin exhibited no cytotoxicity but significantly inhibited EGF-induced migration, as determined using wound healing and Boyden chamber assays. Cotreatment with troglitazone and lovastatin altered the epithelial-to-mesenchymal-transition (EMT) -related marker gene expression of the cells; specifically, E-cadherin expression increased and vimentin expression decreased. In addition, cotreatment reduced the number of filopodia, which are believed to be involved in migration, and significantly inhibited EGF-induced Cyr61 mRNA and protein expression as well as Cyr61 secretion. Moreover, the phosphorylation levels of 2 crucial signal molecules for EGF-induced Cyr61 expression, the cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), were decreased in cells cotreated with troglitazone and lovastatin. Performing a transient transfection assay revealed that the combined treatment significantly suppressed Cyr61 promoter activity. These results suggest that combined treatment with low doses of troglitazone and lovastatin effectively inhibits ATC cell migration and may serve as a novel therapeutic strategy for metastatic ATC.
Highlights
Anaplastic thyroid cancer (ATC) is among the most aggressive malignancies with extremely short survival and poor prognosis
The results indicated that 5 μM troglitazone combined with less than 4 μM lovastatin did not cause cell death in the ATC cells
Our previous studies have revealed that Epidermal growth factor (EGF) can induce cysteine-rich protein 61 (Cyr61) expression through the activation of the epidermal growth factor receptor (EGFR)/ extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB) signaling pathway and that EGF-induced Cyr61 is involved in the regulation of cell migration in ATC cells
Summary
Anaplastic thyroid cancer (ATC) is among the most aggressive malignancies with extremely short survival and poor prognosis. No curative options are available for patients with ATC, and the poor prognosis is attributed to its unlimited growth and invasive migration. Epidermal growth factor (EGF), a ligand of the EGFR, can bind to and activate the EGFR and transduce the proliferation and survival signals primarily mediated by both mitogen-activated protein kinase (MAPK) and phosphatidylinositol-30 kinase (PI3K) [3]. EGF or EGFR overexpression was observed in most thyroid cancer cells, including ATC cells [7]. Increased EGF expression is associated with poor prognosis in patients with metastatic thyroid cancer [7]. A study indicated that the EGFR is a novel therapeutic target for treating patients with ATC [8]
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