Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the invasiveness of endometrial cancer cells through the GnRH-I receptor and mitogen-activated protein kinase (MAPK)-dependent activation of matrix metalloproteinase (MMP)-2.

Abstract

BACKGROUND:

More than 25% of patients diagnosed with endometrial carcinoma have an invasive primary cancer accompanied by metastases. Gonadotropin-releasing hormone (GnRH) plays an important role in reproduction. In mammals, expression of GnRH-II is higher than GnRH-I in reproductive tissues. Here, we examined the effect of a GnRH-II agonist on the motility of endometrial cancer cells and its mechanism of action in endometrial cancer therapy.

METHODS:

Immunoblotting and immunohistochemistry (IHC) were used to determine the expression of the GnRH-I receptor protein in human endometrial cancer. The activity of MMP-2 in the conditioned medium was determined by gelatin zymography. Cell motility was assessed by invasion and migration assay. GnRH-I receptor si-RNA was applied to knockdown GnRH-I receptor.

RESULTS:

The GnRH-I receptor was expressed in the endometrial cancer cells. The GnRH-II agonist promoted cell motility in a dose-dependent manner. The GnRH-II agonist induced the phosphorylation of ERK1/2 and JNK, and the phosphorylation was abolished by ERK1/2 inhibitor (U0126) and the JNK inhibitor (SP600125). Cell motility promoted by GnRH-II agonist was suppressed in cells that were pretreated with U0126 and SP600125. Moreover, U0126 and SP600125 abolished the GnRH-II agonist-induced activation of MMP-2. The inhibition of MMP-2 with MMP-2 inhibitor (OA-Hy) suppressed the increase in cell motility in response to the GnRH-II agonist. Enhanced cell motility mediated by GnRH-II agonist was also suppressed by the knockdown of the endogenous GnRH-I receptor using siRNA.

CONCLUSION:

Our study indicates that GnRH-II agonist promoted cell motility of endometrial cancer cells through the GnRH-I receptor via the phosphorylation of ERK1/2 and JNK, and the subsequent, MAPK-dependent activation of MMP-2. Our findings represent a new concept regarding the mechanism of GnRH-II-induced cell motility in endometrial cancer cells and suggest the possibility of exploring GnRH-II as a potential therapeutic target for the treatment of human endometrial cancer.

• Authors: Hsien-Ming Wu, Hsin-Shih Wang, Hong-Yuan Huang, Chyong-Huey Lai, Chyi-Long Lee, Yung-Kuei Soong, Peter Ck Leung
• Journal: BMC cancer (BMC Cancer) Vol. 13 Pg. 300 (Jun 20 2013) ISSN: 1471-2407 [Electronic] England
• PMID: 23786715 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Butadienes
• GNRHR protein, human
• Hydroxamic Acids
• Nitriles
• Receptors, LHRH
• U 0126
• N-hydroxy-9-octadecenamide
• pyrazolanthrone
• Gonadotropin-Releasing Hormone
• Mitogen-Activated Protein Kinases
• Matrix Metalloproteinase 2

Topics

• Anthracenes (pharmacology)
• Butadienes (pharmacology)
• Carcinoma (metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Endometrial Neoplasms (metabolism, pathology)
• Enzyme Activation (drug effects)
• Female
• Gene Knockdown Techniques
• Gonadotropin-Releasing Hormone (agonists)
• Humans
• Hydroxamic Acids (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Matrix Metalloproteinase 2 (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Neoplasm Invasiveness
• Nitriles (pharmacology)
• Phosphorylation
• Receptors, LHRH (genetics, metabolism)