Endocrine Abstracts (2009) 20 P187

Presence and potential pathophysiological relevance of GOAT, the ghrelin O-acylation enzyme, in human pituitary tumors

Ana Quintero1, Antonio J Martinez-Fuentes1, Carlos Dieguez2, Pedro Benito-Lopez1, Alfonso Leal3, Susan Webb4, Maria M Malagon1, Raul M Luque1 & Justo P Castano1

1University of Cordoba, CIBERobn, Cordoba, Spain; 2University of Santiago de Compostela, Santiago de Compostela, Spain; 3IBIS-Hospital Virgen del Rocio, Sevilla, Spain; 4Hospital Sant Pau, UAB, CIBERER, Barcelona, Spain.

Ghrelin was isolated from stomach by its ability to stimulate growth hormone (GH) release through the GH-secretagogue receptor (GHS-R1a). However, ghrelin/GHS-R expression in multiple tissues and tumor types suggested additional roles for this tandem. Ghrelin, a 28-aminoacid peptide, requires a unique O-acylation at its Ser-3 residue to bind GHS-R1a and release GH. Conversely, unacylated ghrelin (UAG), initially considered inactive, seems to play distinct metabolic roles. Recent identification of GOAT, the enzyme that acylates ghrelin, opens novel strategies to understand and clinically manipulate this axis. Pituitary tumors often express ghrelin and/or GHS-R, yet their pathophysiological relevance is still unclear. To investigate this, expression of GOAT, ghrelin, GHS-R1a, and truncated GHS-R1b was evaluated by qPCR in 35 non-functioning pituitary adenomas (NFPA), 13 somatotropinomas, and seven corticotropinomas. Additionally, functional relevance of ghrelin acylation was assessed by evaluating calcium kinetics in single living somatotropinoma cells in response to acylated ghrelin (AG) or UAG. Results showed that ghrelin was expressed at moderate, comparable levels in the three types of adenomas. Conversely, GOAT expression was higher in somatotropinomas than in NFPA, which expressed similar levels than corticotropinomas. Accordingly, relative GOAT levels only surpassed those of ghrelin in somatotropinomas. GOAT was also expressed in normal human pituitary. GHS-R1a and GHS-R1b were also expressed in all three tumor types, whit somatotropinomas showing the highest GHS-1a levels. GOAT activity can be determinant for ghrelin function, since AG increased [Ca2+]i in single cells derived from three different somatotropinomas, whereas UAG did not alter calcium levels nor affected AG action in these cells. These results demonstrate a differential expression of GOAT in human NFPA, corticotropinomas, and somatotropinomas, and support the notion that, at least in somatotropinomas, GOAT can play a functionally significant role by modulating the effects of ghrelin (AG versus UAG) upon somatotropinoma cells.

Support:BIO139&CTS1705-J. Andalucia;BFU2004-03883&BFU2007-60180-MEC/FEDER-Spain.

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