endothelin-1 and Central-Nervous-System-Neoplasms

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.

Topics: Astrocytes; Cell Line, Tumor; Cell Movement; Cell Nucleus; Central Nervous System Neoplasms; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Glioblastoma; Humans; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 13; Matrix Metalloproteinase 9; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptor, Endothelin A; Receptor, Endothelin B; Transcription Factor AP-1

Endothelin-1 (ET-1) is mitogenic and/or antiapoptotic in human cancers, and antagonists to ET-1 receptors are under evaluation for cancer treatment. Inhibition of ET-1 activation by the endothelin-converting enzymes 1(a)(-)(d) (ECE-1(a)(-)(d); EC 3.4.24.71) represents another approach to block the ET-1 effect in cancer. To evaluate this potential, we synthesized and characterized a series of low nanomolar nonpeptidic thiol-containing ECE-1 inhibitors, and evaluated their effect, as well as the effect of inhibitors for the related metalloproteases neprilysin (NEP; EC 3.4.24.11) and angiotensin-converting enzyme (ACE; EC 3.4.15.1), on human glioblastoma cell growth. Only ECE-1 inhibitors inhibited DNA synthesis by human glioblastoma cells. Exogenous addition of ET-1 or bigET-1 to glioblastoma cells did not counterbalance the growth inhibition elicited by ECE-1 inhibitors, suggesting that ECE-1 inhibitors block the proliferation of human glioblastoma cells most likely via a mechanism not involving extracellular production of ET-1. This class of molecules may thus represent novel therapeutic agents for the potential treatment of human cancer.

Topics: Antineoplastic Agents; Aspartic Acid Endopeptidases; Carbamates; Cell Line, Tumor; Cell Proliferation; Central Nervous System Neoplasms; Drug Screening Assays, Antitumor; Endothelin-1; Endothelin-Converting Enzymes; Glioblastoma; Humans; Hydrazines; Metalloendopeptidases; Proline; Pyrimidines; Pyrrolidines; Structure-Activity Relationship; Sulfhydryl Compounds

It is demonstrated that endothelin-1 (ET-1) is synthesized by and released from certain malignant tumor cells, and it plays an important role in growth and development of tumor. This study was designed to investigate the expression of ET-1 in astrocytomas and the relationship between the ET-1 quantity and the grades of astrocytomas.. ET-1 expression was determined in 70 astrocytoma specimens using Streptavidin-Peroxidase method and image analysis technology.. The ET-1 expressed in all of astrocytomas, and the ET-1 expression was mainly located in the cytoplasm. The positive rates of ET-1 in grade IV and III astrocytomas (86.67% and 93.33%) were significantly higher than that in grade II, I and normal astrocytes(75.00%, 66.67%, and 37.50%) (P < 0.05). The results of image analysis on astrocytoma (grade IV, III, II, I and normal control: 0.1875 +/- 0.0227, 0.1516 +/- 0.0134, 0.1215 +/- 0.0116, 0.1048 +/- 0.0143, and 0.0717 +/- 0.0074, respectively) showed that the lower differentiation of astrocytoma, the higher ET-1 expression (P < 0.01). The expression of ET-1 was significantly correleted with the tumor grading (r = 0.863, P < 0.01).. The ET-1 quantitative analysis may be used as a monitoring index of astrocytoma growing.

Topics: Adolescent; Adult; Aged; Astrocytoma; Central Nervous System Neoplasms; Endothelin-1; Female; Humans; Immunohistochemistry; Male; Middle Aged