Growth hormone-releasing hormone (GHRH) and its agonists inhibit hepatic and tumoral secretion of IGF-1

// Tengjiao Cui 1,2 and Andrew V. Schally 1,2,3,4 1 Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA 2 Department of Medicine, Divisions of Hematology, Oncology and Endocrinology, University of Miami, Miami, FL, USA 3 Department of Pathology, University of Miami, Miami, FL, USA 4 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA Correspondence to: Andrew V. Schally, email: andrew.schally@va.gov Keywords : IGF-1; GHRH agonists; hepatocytes; tumor; JAK2/STAT5 signaling Received: June 01, 2018     Accepted: June 12, 2018     Published: June 19, 2018 Abstract The role of hypothalamic growth hormone-releasing hormone (GHRH) in the release of growth hormone (GH) from the pituitary is well established. However, direct effects of GHRH and its agonistic analogs on extra-pituitary cells and tissues have not been completely elucidated. In the present study, we first demonstrated that human and rat hepatocytes express receptors for GHRH. We then showed that GHRH(1-29)NH 2 and GHRH agonist, MR-409, downregulated mRNA levels for IGF-1 in human cancer cell lines and inhibited IGF-1 secretion in vitro when these cancer lines were exposed to rhGH. Another GHRH agonist, MR-356, lowered serum IGF-l and inhibited tumor growth in nude mice bearing xenografted NCI-N87 human stomach cancers. GHRH(1-29)NH 2 and MR-409 also suppressed the expression of mRNA for IGF-1 and IGF-2 in rat and human hepatocytes, decreased the secretion of IGF-1 in vitro from rat hepatocytes stimulated with rhGH, and lowered serum IGF-l levels in hypophysectomized rats injected with rhGH. Vasoactive intestinal peptide had no effect on the release of IGF-1 from the hepatocytes . Treatment of C57BL/6 mice with MR-409 reduced serum levels of IGF-l from days 1 to 5. These results show that GHRH and its agonists can, by a direct action, inhibit the secretion of IGF-1 from the liver and from tumors. The inhibitory effect of GHRH appears to be mediated by the GHRH receptor (GHRH-R) and GH receptor (GHR), with the involvement of JAK2/STAT5 pathways. Further studies are required to investigate the possible physiopathological role of GHRH in the control of secretion of IGF-1.