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Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway

Harvinder S Chahal1, Giampaolo Trivellin, Chrysanthia A Leontiou

  • 1Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.

The Journal of Clinical Endocrinology and Metabolism
|June 5, 2012
PubMed
Abstract

Insights

Aryl hydrocarbon receptor interacting protein (AIP) may mediate somatostatin analog effectiveness in sporadic somatotroph tumors via ZAC1. This finding could explain treatment resistance in patients with AIP mutations.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Oncology

Background:

  • Somatotroph adenomas with aryl hydrocarbon receptor interacting protein (AIP) mutations show reduced response to somatostatin analogs.
  • This suggests a potential role for AIP in mediating somatostatin analog efficacy.

Purpose of the Study:

  • To investigate the involvement of AIP in the mechanism of action of somatostatin analogs.
  • To explore the relationship between AIP, ZAC1, and somatostatin analog response in somatotroph tumors.

Main Methods:

  • Human study: 16-week lanreotide pretreatment versus no pretreatment in acromegaly patients (n=49).
  • In vitro study: GH3 cell line treated with octreotide or transfected with AIP-targeting siRNA/plasmids.
  • Measurements included hormone levels, tumor volume, AIP and somatostatin receptor expression, ZAC1 expression, and cell proliferation.

Main Results:

  • Lanreotide pretreatment significantly reduced GH, IGF-I, and tumor volume.
  • AIP immunostaining was higher in the lanreotide-pretreated group.
  • Octreotide increased AIP and ZAC1 expression in GH3 cells; AIP modulation affected ZAC1 levels and cell proliferation.
  • AIP mutations did not correlate with reduced somatostatin receptor staining.

Conclusions:

  • AIP appears to mediate somatostatin analog action through ZAC1 in sporadic somatotroph tumors.
  • This mechanism may underlie the limited efficacy of somatostatin analogs in patients with AIP mutations.

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