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J. Biol. Chem., Vol. 281, Issue 24, 16681-16690, June 16, 2006

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Ghrelin and the Growth Hormone Secretagogue Receptor Constitute a Novel Autocrine Pathway in Astrocytoma Motility^*

Vishwa Deep Dixit, Ashani T. Weeraratna, Hyunwon Yang, Dorothy Bertak, Anthony Cooper-Jenkins, Gregory J. Riggins, Charles G. Eberhart, and Dennis D. Taub¹

From the Laboratory of Immunology, NIA Intramural Research Program, National Institutes of Health, and the Departments of Neurosurgery and Pathology, Johns Hopkins University, Baltimore, Maryland 21224

Originally thought of as a stomach-derived endocrine peptide acting via its receptors in the central nervous system to stimulate food intake and growth hormone expression, ghrelin and its receptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ systems, including cancer cells. However, the direct functional role of ghrelin and its receptor in tumors of central nervous system origin remains to be defined. Here, we demonstrate that the human astrocytoma cell lines U-118, U-87, CCF-STTG1, and SW1088 express 6-, 11-, 15-, and 29-fold higher levels of GHS-R compared with primary normal human astrocytes. The ligation of GHS-R by ghrelin on these cells resulted in an increase in intracellular calcium mobilization, protein kinase C activation, actin polymerization, matrix metalloproteinase-2 activity, and astrocytoma motility. In addition, ghrelin led to actin polymerization and membrane ruffling on cells, with the specific co-localization of the small GTPase Rac1 with GHS-R on the leading edge of the astrocytoma cells and imparting the tumor cells with a motile phenotype. Disruption of the endogenous ghrelin/GHS-R pathway by RNA interference resulted in diminished motility, matrix metalloproteinase activity, and Rac expression, whereas tumor cells stably overexpressing GHS-R exhibited increased cell motility. The relevance of ghrelin and GHS-R expression was verified in clinically relevant tissues from 20 patients with oligodendrogliomas and grade II–IV astrocytomas. Analysis of a central nervous system tumor tissue microarray revealed that strong GHS-R and ghrelin expression was significantly more common in high grade tumors compared with low grade ones. Together, these findings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasiveness of cancers of central nervous system origin.

Received for publication, January 10, 2006 , and in revised form, February 17, 2006.

^* This work was supported in part by the NIA Intramural Research Program of the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Clinical Immunology Section, Lab. of Immunology, NIA Intramural Research Program, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8159; Fax: 410-558-8284; E-mail: Taubd{at}grc.nia.nih.gov.

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