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Am J Physiol Endocrinol Metab 293: E302-E309, 2007. First published April 3, 2007; doi:10.1152/ajpendo.00377.2006
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Ghrelin and its unacylated isoform stimulate the growth of adrenocortical tumor cells via an anti-apoptotic pathway

P. J. D. Delhanty,1 P. M. van Koetsveld,1 C. Gauna,1 B. van de Zande,1 G. Vitale,1,2 L. J. Hofland,1 and A. J. van der Lely1

1Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; 2Chair of Endocrinology, Faculty of Medicine, University of Milan, Istituto Auxologico Italiano, Milan, Italy

Submitted 28 July 2006 ; accepted in final form 2 April 2007

Ghrelin is expressed in normal human adrenocortical cells and induces their proliferation through growth hormone secretagogue receptor 1a (GHS-R1a). Consequently, it was of interest to us to determine whether acylated ghrelin and its predominant serum isoform, unacylated ghrelin, also act as factors for adrenocortical carcinoma cell growth. To examine a potential ghrelin-regulated system in adrenocortical tumors, we measured proliferative effects of acylated and unacylated ghrelin in the adrenocortical carcinoma cell lines SW-13 and NCI-H295R. We also examined the expression of ghrelin, GHS-R1a, and corticotrophin-releasing factor receptor 2 (CRF-R2). Acylated and unacylated ghrelin in the nanomolar range dose-dependently induced adrenocortical cell growth up to 200% of untreated controls, as measured by thymidine uptake and WST1 assay. The proliferative effects of acylated and unacylated ghrelin in SW-13 cells was blocked by [D-Lys3]growth hormone-releasing peptide 6 (GHRP6), but a CRF-R2 antagonist had no effect on unacylated ghrelin growth stimulation. Cell cycle analysis suggests that acylated and unacylated ghrelin suppress the sub-G0/apoptotic fraction by up to 50%. Measurement of DNA fragmentation and caspase-3 and -7 activity in SW-13 cells confirmed that acylated and unacylated ghrelin suppress apoptotic rate. SW-13 cells express preproghrelin mRNA and secrete ghrelin, and [D-Lys3]GHRP6 suppresses their basal proliferation rate, strongly suggesting that ghrelin could act as an auto/paracrine growth factor. Acylated and unacylated ghrelin are potential auto/paracrine factors acting through an antiapoptotic pathway to stimulate adrenocortical tumor cell growth. Unacylated ghrelin-stimulated growth is suppressed by an antagonist of GHS-R1a, suggesting either that unacylated ghrelin is acylated before its action or that ghrelin, unacylated ghrelin, and [D-Lys3]GHRP-6 bind to a novel receptor in these cells.

unacylated ghrelin


Address for reprint requests and other correspondence: P. J. D. Delhanty, Dept. of Internal Medicine, Rm. Ee542, Erasmus Medical Centre, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands (e-mail: p.delhanty{at}erasmusmc.nl)






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