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Western Australian Institute for Medical Research, Center for Medical Research, Sir Charles Gairdner Hospital, and Animal Science Group, University of Western Australia, Nedlands, Perth, Western Australia 6009, Australia
Address all correspondence and requests for reprints to: Prof. Karin A. Eidne, Western Australian Institute for Medical Research, B Block, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth, Western Australia 6009, Australia. E-mail: keidne{at}waimr.uwa.edu.au.
Continuous administration of GnRH analogs results in an inhibition of tumor growth that may be mediated in part by direct activation of GnRH receptors (GnRHRs) expressed on tumor cells. However, it is not fully understood how the GnRHR mediates these growth effects. This study aimed to determine how the presence or absence of this receptor in different cell types might affect the ability of GnRH to directly mediate growth effects. We demonstrate that continuous treatment with GnRH or a GnRH agonist (GnRHA) induces an antiproliferative effect in a gonadotrope-derived cell line (LßT2) and also in HEK293 cells stably expressing either the rat or human GnRHR. The antiproliferative effect was time and dose dependent and was verified using [3H]thymidine incorporation, light microscopy, and analysis of cell number. Inhibition was specifically mediated via the GnRHR, as cotreatment of the GnRHR-expressing cell lines with a GnRH antagonist blocked the growth-suppressive effect induced by GnRHA treatment. Cell cycle analysis revealed that GnRHA-treated HEK/GnRHR cell lines induced an accumulation of cells in the G2/M phase, whereas a G0/G1 arrest was observed in LßT2 cells. GnRHA treatment also caused a small, but significant, increase in apoptotic cells. This study provides evidence for a direct role for the GnRHR in mediating antiproliferative events in two cell systems, neither of which was derived from extrapituitary reproductive tumors. The ability to induce these effects, regardless of the cell system involved, has implications regarding the use of GnRH analogs for the treatment of endocrine-related disorders and tumors.
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