SFEBES2009 Oral Communications Neuroendocrine tumours/pituitary (8 abstracts)
A novel mechanism of effect for somatostatin analogues: the role of AIP
Harvinder Chahal 1 , Neda Alband 1 , Olaf Ansorge 2 , Niki Karavitaki 3 , Eivind Carlsen 1 , John Wass 3 , Ashley Grossman 1 & Márta Korbonits 1
1Barts and the London School of Medicine, Centre for Endocrinology, Queen Mary University of London, London, UK; 2Department of Neuropathology, John Radcliffe Hospital, Oxford, UK; 3Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK.
Background: Recently, germline mutations in the aryl-hydrocarbon-receptor-interacting-protein (AIP) gene have been found to occur in familial and sometimes in early onset sporadic somatotroph adenomas. These tumours tend to respond less well to somatostatin analogues (SSA). It has been shown previously that AIP can upregulate the transcription factor Zac1 in liver cells, and we were able to also demonstrate this in pituitary cells. On the other hand, Zac1 is upregulated in response to SSA. Therefore, we have hypothesised that SSA might mediate their effects by a pathway involving AIP and Zac1.
Aim: To study the effect of SSA on AIP and Zac1 expression in patients with sporadic acromegaly and in a somatomammotroph cell line.
Methods: Seventeen patients with sporadic acromegaly were treated with lanreotide 30 mg/1–2 weeks, 16 weeks prior to transsphenoidal surgery. They were matched (age, sex and tumour size) to 17 patients with no pretreatment prior to surgery. AIP protein expression was assessed by immunostaining. GH3 cells treated with 1 nM octreotide were assessed for AIP and Zac1 expression by ‘real time’ PCR and immunoblotting.
Results: AIP immunostaining was significantly increased in the lanreotide group (60.3±19% positive cells) versus the control group (27.9±11.7%) in both sexes (P<0.001). In female patients there was a correlation between AIP staining and the reduction in IGF1 levels after lanreotide treatment (R=−0.66, P<0.05). After treatment of GH3 cells with 1 nM octreotide, both AIP and Zac1 mRNA expression were significantly increased at 6 h (P<0.02), while AIP protein expression was significantly increased at 9 and 12 h (P<0.01).
Conclusion: Our previous data on the lack of effect of SSA in patients with AIP mutations, together with the increased AIP protein expression in somatotrophinomas after SSA pretreatment and the in vitro data on AIP and Zac1 upregulation, suggest that AIP is an important element in mediating the effects of SSA.
Volume 21
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