Abstract | OBJECTIVES:
Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities and a widespread tissue distribution. Ghrelin is the endogenous ligand of the GH secretagogue receptor type 1a (GHS-R1a), and both ghrelin and the GHS-R1a are expressed in the pituitary. There are conflicting data regarding the effects of ghrelin on cell proliferation. A positive effect on proliferation and activation of the mitogen-activated protein kinase (MAPK) pathway has been found in hepatoma, adipose, cardiomyocyte and prostate cell lines. However, ghrelin has also been shown to have anti-proliferative effects on breast, lung and thyroid cell lines. We therefore examined the effect of ghrelin on the rat pituitary cell line GH3. METHODS: RESULTS:
GHS-R1a and ghrelin mRNA expression were detected in GH3 cells. Ghrelin, at 10(-10) to 10(-6) M concentrations, significantly increased [(3)H] thymidine incorporation ( at 10(-9) M, 183+/-13% (means+/-s.e.m.) compared with untreated controls), while 12-phorbol 13-myristate acetate (PMA) at 10(-7) M (used as a positive control) caused a 212+/-14% increase. A reproducible stimulatory effect of desoctanoyl ghrelin was also observed on [(3)H] thymidine incorporation (135+/-5%; P<0.01 at 10(-9) M compared with control), as well as on the cell count (control 6.8 x 10(4)+/-8.7 x 10(3) cells/ml vs desoctanoyl ghrelin (10(-9) M) 1.04 x 10(5)+/-7.5 x 10(3) cells/ml; P<0.01). Ghrelin caused a significant increase in phosphorylated ERK 1/2 in immunoblotting, while desoctanoyl ghrelin showed a smaller but also significant stimulatory effect. The positive effect of ghrelin and desoctanoyl ghrelin on [(3)H] thymidine incorporation was abolished by the MAPK kinase inhibitor U0126, the PKC inhibitor GF109203X and the tyrosine kinase inhibitor tyrphostin 23, suggesting that the ghrelin-induced cell proliferation of GH3 cells is mediated both via a PKC-MAPK-dependent pathway and via a tyrosine kinase-dependent pathway. This could also be clearly demonstrated by Western blot analysis, where a transient increase in ERK 1/2 phosphorylation by ghrelin was attenuated by all three inhibitors. CONCLUSION: We have shown a novel role for ghrelin in stimulating the proliferation of a somatotroph pituitary tumour cell line, suggesting that ERK activation is involved in mediating the effects of ghrelin on cell proliferation. Desoctanoyl ghrelin showed a similar effect. 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.
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Authors | Alexandra M Nanzer, Sahira Khalaf, Abdul M Mozid, Robert C Fowkes, Mayur V Patel, Jacky M Burrin, Ashley B Grossman, Martá Korbonits |
Journal | European journal of endocrinology
(Eur J Endocrinol)
Vol. 151
Issue 2
Pg. 233-40
(Aug 2004)
ISSN: 0804-4643 [Print] England |
PMID | 15296479
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Androstadienes
- Butadienes
- Carcinogens
- Enzyme Inhibitors
- Ghrelin
- Indoles
- Maleimides
- Nitriles
- Peptide Hormones
- Phosphoinositide-3 Kinase Inhibitors
- RNA, Messenger
- Tyrphostins
- U 0126
- bisindolylmaleimide I
- Tetradecanoylphorbol Acetate
- tyrphostin A23
- Wortmannin
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Topics |
- Androstadienes
(pharmacology)
- Animals
- Butadienes
(pharmacology)
- Carcinogens
(pharmacology)
- Cell Division
(drug effects)
- Cell Line, Tumor
(cytology, drug effects)
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Ghrelin
- Indoles
(pharmacology)
- MAP Kinase Signaling System
(drug effects, physiology)
- Maleimides
(pharmacology)
- Nitriles
(pharmacology)
- Peptide Hormones
(genetics, pharmacology)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Phosphoinositide-3 Kinase Inhibitors
- Phosphorylation
(drug effects)
- Pituitary Gland
(cytology, drug effects, enzymology)
- Pituitary Neoplasms
- RNA, Messenger
(analysis)
- Rats
- Tetradecanoylphorbol Acetate
(pharmacology)
- Tyrphostins
(pharmacology)
- Wortmannin
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