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Gonadotropin-releasing hormone promotes ovarian cancer cell invasiveness through c-Jun NH2-terminal kinase-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9.
Gonadotropin-releasing hormone promotes ovarian cancer cell invasiveness through c-Jun NH2-terminal kinase-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9.
- Source :
-
Cancer research [Cancer Res] 2006 Nov 15; Vol. 66 (22), pp. 10902-10. - Publication Year :
- 2006
-
Abstract
- Gonadotropin-releasing hormone (GnRH) receptor is present in 80% of ovarian cancer, and numerous studies have provided evidence for a role of GnRH in cell proliferation. In this study, the effect of GnRH on the invasion potential of ovarian cancer cells was investigated. In vitro migration and cell invasion assays with the ovarian cancer cell lines Caov-3 and OVCAR-3 revealed the biphasic nature of GnRH; low concentrations of GnRH agonist (GnRHa) increased the cell motility and invasiveness of these cells, but at increased concentrations, the stimulatory effect was insignificant. Reverse transcription-PCR, Western blot, and gelatin zymography showed that the expression of metastasis-related proteinases, matrix metalloproteinase (MMP)-2 and MMP-9, was up-regulated and activated by GnRHa. Moreover, we observed that GnRHa was able to transactivate the MMP-2 and MMP-9 promoters. The invasive/migratory phenotype activated by GnRHa can be blocked by specific inhibitors or neutralizing antibodies to MMP-2 and MMP-9. Knockdown of the GnRH receptor using small interfering RNA significantly inhibited the GnRH-induced MMP activation, invasion, and migration. In addition, we showed that the c-Jun NH(2)-terminal kinase, but not extracellular signal-regulated kinase 1/2 or p38 mitogen-activated protein kinase, signaling pathway was critical for GnRH-mediated up-regulation of MMP, cell invasion, and motility. These results indicate for the first time an expanded role for GnRH in other aspects of ovarian tumor progression, such as metastasis, via activation of MMP and the subsequent increase in cell migration and invasion.
- Subjects :
- Cell Line, Tumor
Cell Movement drug effects
Cell Movement physiology
Enzyme Activation drug effects
Enzyme Induction drug effects
Female
Humans
Matrix Metalloproteinase 2 biosynthesis
Matrix Metalloproteinase 2 genetics
Matrix Metalloproteinase 9 biosynthesis
Matrix Metalloproteinase 9 genetics
Matrix Metalloproteinase Inhibitors
Neoplasm Invasiveness
Ovarian Neoplasms genetics
RNA, Messenger biosynthesis
RNA, Messenger genetics
RNA, Small Interfering genetics
Receptors, LHRH biosynthesis
Receptors, LHRH genetics
Signal Transduction drug effects
Transfection
Up-Regulation drug effects
Gonadotropin-Releasing Hormone pharmacology
JNK Mitogen-Activated Protein Kinases metabolism
Matrix Metalloproteinase 2 metabolism
Matrix Metalloproteinase 9 metabolism
Ovarian Neoplasms enzymology
Ovarian Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 66
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 17108127
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-06-2217