title: Exogenous endothelin-1 induces cell migration and matrix metalloproteinase expression in U251 human glioblastoma multiforme.
abstract: Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor characterized by its rapid infiltration to surrounding tissues during the early stages. The fast spreading of GBM obscures the initiation of the tumor mass making the treatment outcome undesirable. Endothelin-1 is known as a secretory protein presented in various types of brain cells, which has been indicated as a factor for cancer pathology. The aim of the present study was to investigate the molecular mechanism of cell migration in GBM. We found that various malignant glioma cells expressed higher amounts of endothelin-1, ETA, and ETB receptors than nonmalignant human astrocytes. The application of endothelin-1 enhanced the migratory activity in human U251 glioma cells corresponding to increased expression of matrix metalloproteinase (MMP)-9 and MMP-13. The endothelin-1-induced cell migration was attenuated by MMP-9 and MMP-13 inhibitors and inhibitors of mitogen-activated protein (MAP) kinase and PI3 kinase/Akt. Furthermore, the elevated levels of phosphate c-Jun accumulation in the nucleus and activator protein-1 (AP-1)-DNA binding activity were also found in endothelin-1 treated glioma cells. In migration-prone sublines, cells with greater migration ability showed higher endothelin-1, ETB receptor, and MMP expressions. These results indicate that endothelin-1 activates MAP kinase and AP-1 signaling, resulting in enhanced MMP-9 and MMP-13 expressions and cell migration in GBM.
authors.affiliation: Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Wen-Tsong
authors.initials: WT
authors.lastname: Hsieh
authors.affiliation: Department of Cell and Tissue Engineering and Department of Medical Research, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Wei-Lan
authors.initials: WL
authors.lastname: Yeh
authors.affiliation: Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Ruo-Yuo
authors.initials: RY
authors.lastname: Cheng
authors.affiliation: Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chingju
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Department of Neurosurgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan.
authors.forename: Bor-Ren
authors.initials: BR
authors.lastname: Huang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Caren Yu-Ju
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiang-Suo
authors.initials: SS
authors.lastname: Huang
authors.affiliation: Graduate Institute of Neural and Cognitive Sciences, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan. dahyuu@mail.cmu.edu.tw.
authors.forename: Dah-Yuu
authors.initials: DY
authors.lastname: Lu
mesh_terms: D001253:Astrocytes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D016543:Central Nervous System Neoplasms / Q000503:physiopathology*; D019332:Endothelin-1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005909:Glioblastoma / Q000503:physiopathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D018808:Transcription Factor AP-1; C507079:MMP13 protein, human; C579270:MMP9 protein, human
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