Inhibitory Effects of Antagonists of Growth Hormone-Releasing Hormone (GHRH) in Thyroid Cancer
- 170 Downloads
Growth hormone-releasing hormone (GHRH) is a peptide hormone secreted by the hypothalamus that regulates the synthesis and secretion of growth hormone (GH) in the pituitary. The extra-hypothalamic GHRH and its cognate receptors (GHRHR and splice variants) play a mitogenic role by stimulating cell proliferation and preventing apoptotic cell death. It is well established that GHRH antagonists inhibit the growth, tumorigenicity, and metastasis of various human malignancies. In this work, we studied the effect of two new GHRH antagonists, MIA602 and MIA690, on thyroid cancer. We studied the effect of MIA602 and MIA690 on thyroid cancer in vitro, using human thyroid cancer cell lines, and in vivo, using chicken embryo chorioallantoic membrane (CAM) assays. We found that mRNA for GHRH and GHRH receptor is expressed in thyroid cell lines and in samples of thyroid tumors. Immunohistochemistry confirmed the expression of GHRHR protein in specimens of thyroid tumor. We observed that GHRH antagonists inhibited the growth and increased apoptosis of thyroid cancer cells. In vivo, the antagonists inhibited growth and angiogenesis of engrafted thyroid tumors. Our results suggest that GHRH expression may play a role in growth of thyroid cancer and that GHRH antagonists can be a therapeutic option for thyroid cancer patients.
KeywordsThyroid cancer Growth hormone-releasing hormone GHRH antagonists Hypothalamic hormone mRNA for GHRH mRNA for GHRH receptors
This study was supported by the Portuguese Foundation for Science and Technology through a Post-Doc grant to HP (ref.: SFRH/BPD/85249/2012). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT. This work was financed by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). Further funding was obtained from the project “Advancing cancer research: from basic knowledgment to application”;NORTE-01-0145-FEDER-000029; “Projetos Estruturados de I&D&I,” funded by Norte 2020-Programa Operacional Regional do Norte. A.V.S. was supported by the Medical Research Service of the Department of Veterans Affairs and Department of Medicine, Division of Hematology-Oncology and Sylvester Comprehensive Cancer Center, University of Miami, School of Medicine.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest
- 1.Busto R, Schally AV, Varga JL, Garcia-Fernandez MO, Groot K, Armatis P, Szepeshazi K (2002) The expression of growth hormone-releasing hormone (GHRH) and splice variants of its receptor in human gastroenteropancreatic carcinomas. Proc Natl Acad Sci U S A 99:11866–11871CrossRefPubMedPubMedCentralGoogle Scholar
- 2.Catanuto P, Tashiro J, Rick FG, Sanchez P, Solorzano CC, Glassberg MK, Block NL, Lew JI, Elliot SJ, Schally AV (2015) Expression of receptors for pituitary-type growth hormone-releasing hormone (pGHRH-R) in human papillary thyroid cancer cells: effects of GHRH antagonists on matrix Metalloproteinase-2. Horm Cancer 6:100–106CrossRefPubMedGoogle Scholar
- 3.Fahrenholtz CD, Rick FG, Garcia MI, Zarandi M, Cai RZ, Block NL, Schally AV, Burnstein KL (2014) Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer. Proc Natl Acad Sci U S A 111:1084–1089CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Havt A, Schally AV, Halmos G, Varga JL, Toller GL, Horvath JE, Szepeshazi K, Koster F, Kovitz K, Groot K, Zarandi M, Kanashiro CA (2005) The expression of the pituitary growth hormone-releasing hormone receptor and its splice variants in normal and neoplastic human tissues. Proc Natl Acad Sci U S A 102:17424–17429CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Hohla F, Moder A, Mayrhauser U, Hauser-Kronberger C, Schally AV, Varga JL, Zarandi M, Buchholz S, Huber R, Aigner E, Ritter M, Datz C (2008) Differential expression of GHRH receptor and its splice variant 1 in human normal and malignant mucosa of the oesophagus and colon. Int J Oncol 33:137–143PubMedGoogle Scholar
- 15.Rick FG, Schally AV, Block NL, Nadji M, Szepeshazi K, Zarandi M, Vidaurre I, Perez R, Halmos G, Szalontay L (2011) Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia. Proc Natl Acad Sci U S A 108:3755–3760CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Rick FG, Schally AV, Szalontay L, Block NL, Szepeshazi K, Nadji M, Zarandi M, Hohla F, Buchholz S, Seitz S (2012) Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases. Proc Natl Acad Sci U S A 109:1655–1660CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Zarandi M, Cai R, Kovacs M, Popovics P, Szalontay L, Cui T, Sha W, Jaszberenyi M, Varga J, Zhang X, Block NL, Rick FG, Halmos G, Schally AV (2017) Synthesis and structure-activity studies on novel analogs of human growth hormone releasing hormone (GHRH) with enhanced inhibitory activities on tumor growth. Peptides 89:60–70CrossRefPubMedGoogle Scholar