Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.

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Antitumor effects of growth hormone-releasing hormone (GHRH) antagonists in ACTH and GH-secreting pituitary adenoma cell lines

Endocrine Abstracts ◽

10.1530/endoabs.63.p266 ◽

2019 ◽

Author(s):

Alessandro Fanciulli ◽

Iacopo Gesmundo ◽

Giacomo Gamba ◽

Justo P Castano ◽

Raul M Luque ◽

...

Keyword(s):

Growth Hormone ◽

Pituitary Adenoma ◽

Cell Lines ◽

Growth Hormone Releasing Hormone ◽

Antitumor Effects ◽

Releasing Hormone ◽

Adenoma Cell ◽

Ghrh Antagonists

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Arginine Counteracts the Inhibitory Effect of Recombinant Human Insulin-Like Growth Factor I on the Somatotroph Responsiveness to Growth Hormone-Releasing Hormone in Humans1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.10.6872 ◽

2000 ◽

Vol 85 (10) ◽

pp. 3604-3608 ◽

Cited By ~ 1

Author(s):

Laura Gianotti ◽

Mauro Maccario ◽

Fabio Lanfranco ◽

Josefina Ramunni ◽

Lidia Di Vito ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Human Insulin ◽

Inhibitory Effect ◽

Insulin Like Growth Factor ◽

Growth Hormone Releasing Hormone ◽

Recombinant Human Insulin ◽

Releasing Hormone ◽

Factor I ◽

Growth Factor I

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Inhibitory Effect of Amylin on Growth Hormone Responsiveness to Growth-Hormone-Releasing Hormone in the Rat

Neuroendocrinology ◽

10.1159/000127019 ◽

1995 ◽

Vol 62 (3) ◽

pp. 313-318 ◽

Cited By ~ 4

Author(s):

Carmela Netti ◽

Valeria Sibilia ◽

Francesca Pagani ◽

Norma Lattuada ◽

Mariella Coluzzi ◽

...

Keyword(s):

Growth Hormone ◽

Inhibitory Effect ◽

Growth Hormone Releasing Hormone ◽

Releasing Hormone ◽

Hormone Responsiveness

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Potent and specific MTH1 inhibitors targeting gastric cancer

Cell Death and Disease ◽

10.1038/s41419-019-1665-3 ◽

2019 ◽

Vol 10 (6) ◽

Cited By ~ 6

Author(s):

Wenjuan Zhou ◽

Liying Ma ◽

Jing Yang ◽

Hui Qiao ◽

Lingyu Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Malignant Tumors ◽

Inhibitory Effect ◽

Human Gastric Cancer ◽

Gastric Cancer Cells ◽

Dntp Pool ◽

Cancer Tissues

Abstract Human mutT homolog 1(MTH1), the oxidized dNTP pool sanitizer enzyme, has been reported to be highly expressed in various malignant tumors. However, the oncogenic role of MTH1 in gastric cancer remains to be determined. In the current study, we found that MTH1 was overexpressed in human gastric cancer tissues and cells. Using an in vitro MTH1 inhibitor screening system, the compounds available in our laboratory were screened and the small molecules containing 5-cyano-6-phenylpyrimidine structure were firstly found to show potently and specifically inhibitory effect on MTH1, especially compound MI-743 with IC50 = 91.44 ± 1.45 nM. Both molecular docking and target engagement experiments proved that MI-743 can directly bind to MTH1. Moreover, MI-743 could not only inhibit cell proliferation in up to 16 cancer cell lines, especially gastric cancer cells HGC-27 and MGC-803, but also significantly induce MTH1-related 8-oxo-dG accumulation and DNA damage. Furthermore, the growth of xenograft tumours derived by injection of MGC-803 cells in nude mice was also significantly inhibited by MI-743 treatment. Importantly, MTH1 knockdown by siRNA in those two gastric cancer cells exhibited the similar findings. Our findings indicate that MTH1 is highly expressed in human gastric cancer tissues and cell lines. Small molecule MI-743 with 5-cyano-6-phenylpyrimidine structure may serve as a novel lead compound targeting the overexpressed MTH1 for gastric cancer treatment.

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Arginine Counteracts the Inhibitory Effect of Recombinant Human Insulin-Like Growth Factor I on the Somatotroph Responsiveness to Growth Hormone-Releasing Hormone in Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.85.10.3604 ◽

2000 ◽

Vol 85 (10) ◽

pp. 3604-3608 ◽

Cited By ~ 6

Author(s):

L. Gianotti

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Human Insulin ◽

Inhibitory Effect ◽

Insulin Like Growth Factor ◽

Growth Hormone Releasing Hormone ◽

Recombinant Human Insulin ◽

Releasing Hormone ◽

Factor I ◽

Growth Factor I

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Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1818865116 ◽

2019 ◽

Vol 116 (6) ◽

pp. 2226-2231 ◽

Cited By ~ 10

Author(s):

Tania Villanova ◽

Iacopo Gesmundo ◽

Valentina Audrito ◽

Nicoletta Vitale ◽

Francesca Silvagno ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Cell Lines ◽

Malignant Pleural Mesothelioma ◽

Pleural Mesothelioma ◽

Growth Hormone Releasing Hormone ◽

Releasing Hormone ◽

Ghrh Antagonists

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.

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Growth Hormone-Releasing Hormone in Lung Physiology and Pulmonary Disease

Cells ◽

10.3390/cells9102331 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2331

Author(s):

Chongxu Zhang ◽

Tengjiao Cui ◽

Renzhi Cai ◽

Medhi Wangpaichitr ◽

Mehdi Mirsaeidi ◽

...

Keyword(s):

Growth Hormone ◽

Therapeutic Potential ◽

Dependent Manner ◽

Growth Hormone Releasing Hormone ◽

Releasing Hormone ◽

Lung Physiology ◽

Extracellular Signal ◽

P21 Activated Kinase

Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases.

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