Activation of human gonadotropin-releasing hormone receptor promotes down regulation of ARHGAP18 and regulates the cell invasion of MDA-MB-231 cells

• Published in: Molecular and cellular endocrinology Vol. 460; pp. 94 - 103
• Main Authors: Aguilar-Rojas, Arturo, Maya-Núñez, Guadalupe, Huerta-Reyes, Maira, Pérez-Solis, Marco Allán, Silva-García, Raúl, Guillén, Nancy, Olivo-Marin, Jean-Christophe
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.01.2018
• Subjects: ARHGAP18; Breast cancer; Cell Adhesion; Cell invasion; Cell Line, Tumor; Cell Proliferation; Collagen Type I - metabolism; Down-Regulation - genetics; Gene Expression Regulation, Neoplastic; Gonadotropin-Releasing Hormone (GnRH); Gonadotropin-Releasing Hormone Receptor (GnRHR); GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humans; Neoplasm Invasiveness; Receptors, LHRH - metabolism; Reproducibility of Results; RhoA GTPase; Wound Healing; Gonadotropin-Releasing Hormone Receptor (GnRHR); ARHGAP18; Breast cancer; Cell invasion; RhoA GTPase; Gonadotropin-Releasing Hormone (GnRH)
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2017.07.009

The Gonadotropin-Releasing Hormone Receptor (GnRHR) is expressed mainly in the gonadotrope membrane of the adenohypophysis and its natural ligand, the Gonadotropin-Releasing Hormone (GnRH), is produced in anterior hypothalamus. Furthermore, both molecules are also present in the membrane of cells derived from other reproductive tissues such as the breast, endometrium, ovary, and prostate, as well as in tumors derived from these tissues. The functions of GnRH receptor and its hormone in malignant cells have been related with the decrease of proliferation and the invasiveness of those tumors however, little is known about the molecules associated with the signaling pathways regulated by both molecules in malignant cells. To further analyze the potential mechanisms employed by the GnRHR/GnRH system to reduce the tumorigenesis of the highly invasive breast cancer cell line MDA-MB-231, we performed microarrays experiments to evaluated changes in genes expression and validate these modifications by functional assays. We show that activation of human GnRHR is able to diminish the expression and therefore functions of the Rho GTPase-Activating Protein 18 (ARHGAP18). Decrease of this GAP following GnRHR activation, correlates to the higher of cell adhesion and also with reduction of tumor cell invasion, supporting the notion that GnRHR triggers intracellular signaling pathways that acts through ARHGAP18. On the contrary, although a decline of cellular proliferation was observed during GnRHR activation in MDA-MB-231, this was independent of ARHGAP18 showing the complex system in which is involved the signaling pathways regulated by the GnRHR/GnRH system. •Activation of human GnRHR, promote the diminution at transcriptional and translational level of the GAP protein, ARHGAP18.•Decrease in GAP, correlates with increase in cell adhesion and decrease in cell invasion evoked by the activation of GnRHR.•The information showed, supports the notion that GnRHR triggers intracellular signaling pathways that acts through ARHGAP18.•The effects of GnRHR on cell proliferation could include signaling pathways independents of ARHGAP18.