Ghrelin, a newly discovered and unique peptide hormone activates the growth hormone secretagogue receptor (GHS-R) to potently induce growth hormone release. Ghrelin treatment rapidly increases serum growth hormone concentrations, as well as stimulating food intake in vivo. Our laboratory was the first to demonstrate that ghrelin increases the proliferation of the prostate cancer cell lines PC3 and LNCaP in vitro and that these cells express the GHS-R at the mRNA and protein level. Since our discovery, other groups have shown that other cancer cell lines including the HepG2 hepatoma cell line display increased proliferation after ghrelin treatment. We also report the identification of a new exon 3-deleted proghrelin human mRNA variant and an equivalent homologue in the mouse. The deletion of exon 3 results in a frameshift and the generation of a unique C-terminal peptide sequence. Using RT-PCR and immunohistochemistry, we have shown that this variant is expressed by a wide range of hormone-dependent carcinoma cell lines and cancer tissues including prostate, breast and endometrial cancers. By employing an antibody generated against the unique exon 3-deleted proghrelin peptide sequence, we have demonstrated immunoreactivity for this variant in normal and malignant prostate glands. Staining intensity in the malignant prostate glands is greater than in normal prostate tissue. This peptide is also expressed in the glands and stroma of breast cancer tissues, with high-grade carcinoma specimens exhibiting the most intense staining. Normal breast sections displayed weak glandular staining and no stromal staining. In conclusion, ghrelin and the novel exon 3-deleted isoform are expressed in hormone-dependent cancers and we have discovered that ghrelin increases the proliferation of prostate cancer cells in vitro. Ghrelin potentially plays an autocrine/paracrine mitogenic role in these tissues and therefore may be a target for therapeutic blockade.
03 - 05 Nov 2003
Society for Endocrinology