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

Tengjiao Cui; Andrew V. Schally

doi:10.18632/oncotarget.25676

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

Tengjiao Cui, Andrew V. Schally

Pathology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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)NH2 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)NH2 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.

Original language	English (US)
Pages (from-to)	28745-28756
Number of pages	12
Journal	Oncotarget
Volume	9
Issue number	47
DOIs	https://doi.org/10.18632/oncotarget.25676
State	Published - Jun 19 2018

Keywords

GHRH agonists
Hepatocytes
IGF-1
JAK2/STAT5 signaling
Tumor

ASJC Scopus subject areas

Oncology

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@article{71b723f71efa4430ba96f46042a8ac1c,

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

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)NH2 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)NH2 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.",

keywords = "GHRH agonists, Hepatocytes, IGF-1, JAK2/STAT5 signaling, Tumor",

author = "Tengjiao Cui and Schally, {Andrew V.}",

note = "Funding Information: We thank Dr. Norman L. Block for editorial advice and assistance and Jinlin He for technical assistance. We are grateful to Dr. Renzhi Cai and Wei Sha for synthesizing GHRH agonists MR-409 and MR-356. This work was supported by the Medical Research Service of the U.S. Department of Veterans Affairs, and by Sylvester Comprehensive Cancer Center of the Miller School of Medicine, University of Miami, all to AVS. The contents do not represent the views of U.S. Department of Veterans Affairs. Publisher Copyright: {\textcopyright}Cui et al. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

year = "2018",

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doi = "10.18632/oncotarget.25676",

language = "English (US)",

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T1 - Growth hormone-releasing hormone (GHRH) and its agonists inhibit hepatic and tumoral secretion of IGF-1

AU - Cui, Tengjiao

AU - Schally, Andrew V.

N1 - Funding Information: We thank Dr. Norman L. Block for editorial advice and assistance and Jinlin He for technical assistance. We are grateful to Dr. Renzhi Cai and Wei Sha for synthesizing GHRH agonists MR-409 and MR-356. This work was supported by the Medical Research Service of the U.S. Department of Veterans Affairs, and by Sylvester Comprehensive Cancer Center of the Miller School of Medicine, University of Miami, all to AVS. The contents do not represent the views of U.S. Department of Veterans Affairs. Publisher Copyright: ©Cui et al. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2018/6/19

Y1 - 2018/6/19

N2 - 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)NH2 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)NH2 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.

AB - 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)NH2 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)NH2 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.

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KW - JAK2/STAT5 signaling

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