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This version published online on October 9, 2003
Endocrinology, doi:10.1210/en.2003-0551
A more recent version of this article appeared on January 1, 2004
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Submitted on May 2, 2003
Accepted on September 25, 2003

GnRH receptor-mediated growth suppression of immortalized L{beta}T2 gonadotrope and stable HEK293 cell lines

Lauren E. C. Miles1, Aylin C. Hanyaloglu1, Jasmin R. Dromey1, Kevin D. G. Pfleger1, and Karin A. Eidne1*

1 Western Australian Institute for Medical Research (WAIMR), Centre for Medical Research, The University of Western Australia, Sir Charles Gairdner Hospital, Nedlands, Australia. Animal Science Group, The University of Western Australia, Perth, Australia

* To whom correspondence should be addressed. E-mail: keidne{at}waimr.uwa.edu.au.

Continuous administration of GnRH analogs results in an inhibition of tumor growth that may, in part, be mediated 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 anti-proliferative effect in a gonadotrope-derived cell line (L{beta}T2) and also in HEK293 cells stably expressing either the rat or human GnRHR. The anti-proliferative 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 co-treatment of the GnRHR-expressing cell lines with a GnRH antagonist blocked the growth suppressive effect induced by GnRHA treatment. Cell cycle analysis revealed that the GnRHA treated HEK/GnRHR cell lines induced an accumulation of cells in the G2/M phase while a G0/G1 arrest was observed in L{beta}T2 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 anti-proliferative events in two cell systems neither of which were derived from extra-pituitary reproductive tumors. The ability to induce these effects, irrespective of the cell system involved, has implications regarding the use of GnRH analogs for the treatment of endocrine-related disorders and tumors.
Key words: gonadotropin-releasing hormone • gonadotropin-releasing hormone receptor • GPCR • G-protein coupled receptor • L{beta}T2 cells • apoptosis • cell cycle arrest • cell proliferation




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