Journal of Neuro-Oncology

, Volume 118, Issue 2, pp 257–269 | Cite as

Exogenous endothelin-1 induces cell migration and matrix metalloproteinase expression in U251 human glioblastoma multiforme

  • Wen-Tsong Hsieh
  • Wei-Lan Yeh
  • Ruo-Yuo Cheng
  • Chingju Lin
  • Cheng-Fang Tsai
  • Bor-Ren Huang
  • Caren Yu-Ju Wu
  • Hsiao-Yun Lin
  • Shiang-Suo Huang
  • Dah-Yuu Lu
Laboratory Investigation


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.


Endothelin-1 Migration MMP Glioblastoma multiforme AP-1 



This work was supported by grants from the National Science Council (NSC 102-2320-B-039-026-MY3, 102-2320-B-039-051-MY3 and 101-2320-B-039-048-MY2), China Medical University (CMU 102-S-21 and CMU 102-AWARD-02), ASIA University (98-ASIA-07-2), and Taichung Tzu Chi General Hospital (TTCRD 101-03). The authors thank Dr. Wei-Hwa Lee (Tri-service General Hospital, Taipei, Taiwan) for kindly provided GBM 8901 cells.

Conflict of interest

The authors report no biomedical financial interests or potential conflicts of interest.

Supplementary material

11060_2014_1442_MOESM1_ESM.doc (618 kb)
Supplementary material 1 (DOC 618 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Wen-Tsong Hsieh
    • 1
  • Wei-Lan Yeh
    • 2
  • Ruo-Yuo Cheng
    • 1
  • Chingju Lin
    • 3
  • Cheng-Fang Tsai
    • 4
  • Bor-Ren Huang
    • 5
  • Caren Yu-Ju Wu
    • 6
  • Hsiao-Yun Lin
    • 7
  • Shiang-Suo Huang
    • 8
  • Dah-Yuu Lu
    • 9
  1. 1.Department of Pharmacology, School of MedicineChina Medical UniversityTaichungTaiwan
  2. 2.Department of Cell and Tissue Engineering and Department of Medical ResearchChanghua Christian HospitalChanghuaTaiwan
  3. 3.Department of Physiology, School of MedicineChina Medical UniversityTaichungTaiwan
  4. 4.Department of BiotechnologyAsia UniversityTaichungTaiwan
  5. 5.Department of NeurosurgeryTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationTaichungTaiwan
  6. 6.Graduate Institute of Basic Medical ScienceChina Medical UniversityTaichungTaiwan
  7. 7.Department of Life SciencesNational Chung Hsing UniversityTaichungTaiwan
  8. 8.Department of Pharmacology and Institute of Medicine, College of MedicineChung Shan Medical UniversityTaichungTaiwan
  9. 9.Graduate Institute of Neural and Cognitive SciencesChina Medical UniversityTaichungTaiwan

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