Growth hormone releasing hormone induces the expression of nitric oxide synthase.
Growth hormone releasing hormone (GHRH) and its receptors are expressed in a wide variety of human tumours and established cancer cell lines and are involved in carcinogenesis. In addition, GHRH antagonists exert an antitumour activity in experimental cancer models. Recent studies indicate that the mechanisms involved in the mediation of the effects of GHRH include the regulation of the metabolism of the reactive oxygen species. This work demonstrates the expression of GHRH receptors and GHRH in the A549 human lung cancer cell line and shows that the mitogenic effect of GHRH in these cells is dependent on the activation of the extracellular receptor kinase (ERK)1/2 pathway. The action of GHRH can be suppressed by GHRH antagonist MZ-5-156 and mitogen activated protein kinase (MAPK) inhibitor PD 098059. These results are reflected in the effect in the proliferating cell nuclear antigen. In addition, our study shows that GHRH increases the expression of the inducible nitric oxide synthase, an enzyme which is strongly involved in various human diseases, including cancer and augments key intracellular regulators of its expression, such as pNF (nuclear factor)κBp50 and cyclooxygenase 2. GHRH antagonist MZ-5-156 counteracts the effects of GHRH in these studies, indicating that this class of peptide antagonists may be useful for the treatment of diseases related to increased oxidative and nitrosative stress.
Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125, USA.
Nektarios
N
Barabutis
Agnieszka
A
Siejka
Andrew V
AV
Schally
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017337:Sermorelin / Q000031:analogs & derivatives / Q000494:pharmacology
D005419:Flavonoids; C106656:MZ 5-156; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D017382:Reactive Oxygen Species; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one