Abstract
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.
Highlights
Ghrelin, a 28-amino acid acylated orexigenic peptide, is believed to be largely secreted from X/A-like cells of the stomach [1, 2]
Similar to other GPCRs, ghrelin treatment of astrocytoma cells induced a marked increase in actin polymerization along with membrane ruffling and development of structures resembling lamellipodia compared with the vehicle control (Fig. 2A)
Because activation of protein kinase C (PKC) downstream of intracellular calcium release is associated with cytoskeletal changes as well as with increases in motility and invasion in several cancers, including melanoma [41], colon carcinoma [46], breast carcinoma [47], and glioma [45], we examined whether ghrelin activates PKC in astrocytoma cells
Summary
A 28-amino acid acylated orexigenic peptide, is believed to be largely secreted from X/A-like cells of the stomach [1, 2]. The post-translational acyl modification of ghrelin is believed to be critical for its ability to bind to GHS-R and to mediate its biological activities [1, 7]. Given that this octanoic group confers hydrophobicity to the N terminus of ghrelin, it may be that this group is responsible for specific targeting of ghrelin to lipid rafts [8] and for its efficient transport across the blood-brain barrier [9]. The growth hormone-releasing hormone/GH/IGF axis has been most widely studied in the development and progression of various cancers, including tumors of the central nervous system [21,22,23]. Little is known about the expression of ghrelin or GHS-R in central nervous system cancers
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