Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis.
Somatostatin (SRIF) analogs provide safe and effective therapy for acromegaly. In a proportion of patients, however, SRIF analogs may lead to discordant growth hormone (GH) and IGF-I suppression, which suggests a more complex mechanism than attributable to inhibition of GH release alone. To elucidate whether SRIF acts peripherally on the GH-IGF-I axis, we showed that rat hepatocytes express somatostatin receptor subtypes-2 and -3 and that IGF-I mRNA and protein levels were suppressed in a dose-dependent manner by administration of octreotide. The inhibitory effect of SRIF was not apparent without added GH and in the presence of GH was specific for IGF-I induction and did not inhibit GH-induced c-myc or extracellular signal regulated kinase (ERK) phosphorylation. Pertussis toxin treatment of hepatocytes incubated with GH and SRIF, or with GH and octreotide, abrogated the inhibitory effect on GH-induced IGF-I, which confirms the requirement for the inhibitory G-protein. Treatment with SRIF and GH increased protein tyrosine phosphatase (PTP) activity and inhibited signal transducer and activator of transcription-5b (STAT5b) phosphorylation and nuclear localization. Octreotide also inhibited GH-stimulated IGF-I protein content of ex vivo-perfused rat livers. The results demonstrate that SRIF acts both centrally and peripherally to control the GH-IGF-I axis, providing a mechanistic explanation for SRIF analog action in treating patients with GH-secreting pituitary adenomas.
Murray
Robert D
RD
Department of Medicine, Cedars Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA.
Kim
Kiwon
K
Ren
Song-Guang
SG
Chelly
Marjorie
M
Umehara
Yutaka
Y
Melmed
Shlomo
S
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D013006:Growth Hormone / Q000032:analysis*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006728:Hormones / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D008894:Milk Proteins; D015282:Octreotide / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000378:metabolism; D050799:STAT5 Transcription Factor; D013004:Somatostatin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D006728:Hormones; D008894:Milk Proteins; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C494097:Stat5b protein, rat; D015534:Trans-Activators; C103631:somatostatin receptor 3; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C093733:somatostatin receptor 2; D037342:Pertussis Toxin; D017027:Protein Tyrosine Phosphatases; D015282:Octreotide