Endocrine Abstracts

BACKGROUND: Ghrelin is a novel 28-amino acid peptide which was isolated from the rat stomach and has now been shown to have a widespread tissue distribution. Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), and stimulates growth hormone (GH) release via the hypothalamus as well as by a direct action on the pituitary GHS-R1a. Ghrelin and the GHS-R1a also coexist within the pituitary. There are conflicting data regarding the effects of ghrelin and growth hormone secretagogues on cell proliferation. Some data suggest anti-proliferative effects on breast and thyroid tissue, while reports on adipose, prostate and liver cells have found increased proliferation and activation of the mitogen activated protein kinase (MAPK) pathway by ghrelin. We have therefore examined the possibility that ghrelin has a proliferative effect on pituitary cells.

METHODS: RT-PCR was used for the detection of GHS-R1a mRNA expression in the GH3 rat pituitary somatotroph cell line. The effect of ghrelin on cell proliferation was studied using [³H]-thymidine incorporation, while Western blotting was performed for phosphorylated and total MAPK.

RESULTS: GHS-R1a mRNA was detected in GH3 cells using RT-PCR. Epidermal growth factor (positive control) caused an expected increase in [³H]-thymidine incorporation (51 ± 7 % above untreated controls; mean ± SEM) by GH3 cells. Ghrelin, 10^-9 and 10^-6 M, dose-dependently significantly increased [³H]-thymidine incorporation by 24 ± 6 % and 44.6 ± 5 % above untreated controls respectively, suggesting increased cell proliferation of GH3 cells in vitro by ghrelin. Ghrelin was also shown to cause activation of the MAPK pathway suggesting this as a possible mechanism for the increase in cell proliferation in GH3 cells.

CONCLUSIONS: In conclusion, we have shown a novel role for ghrelin in stimulating proliferation of a somatotroph pituitary tumour cell line; as ghrelin has been shown to be expressed in both normal and adenomatous pituitary tissue, locally-produced ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway.