Combined treatment with troglitazone and lovastatin inhibited epidermal growth factor-induced migration through the downregulation of cysteine-rich protein 61 in human anaplastic thyroid cancer cells.
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.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Li-Han
LH
Chin
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Sung-Po
SP
Hsu
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Wen-Bin
WB
Zhong
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Traditional Herbal Medicine Research Center, Taipei Medical University, Taipei, Taiwan.
Yu-Chih
YC
Liang
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002839:Chromans / Q000008:administration & dosage* / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008148:Lovastatin / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000494:pharmacology; D065646:Thyroid Carcinoma, Anaplastic / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D000077288:Troglitazone
C501848:CCN1 protein, human; D002839:Chromans; D017362:Cyclic AMP Response Element-Binding Protein; D055515:Cysteine-Rich Protein 61; D045162:Thiazolidinediones; D004815:Epidermal Growth Factor; D008148:Lovastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D000077288:Troglitazone