Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway.
BACKGROUND
Somatotroph adenomas harboring aryl hydrocarbon receptor interacting protein (AIP) mutations respond less well to somatostatin analogs, suggesting that the effects of somatostatin analogs may be mediated by AIP.


OBJECTIVE
The objective of the investigation was to study the involvement of AIP in the mechanism of effect of somatostatin analogs.


METHODS
In the human study, a 16-wk somatostatin analog pretreatment compared with no pretreatment. In the in vitro cell line study, the effect of somatostatin analog treatment or small interfering RNA (siRNA)/plasmid transfection were studied.


METHODS
The study was conducted at a university hospital.


METHODS
Thirty-nine sporadic and 10 familial acromegaly patients participated in the study.


METHODS
Interventions included preoperative lanreotide treatment and pituitary surgery.


RESULTS
For the human study, GH and IGF-I levels, AIP, and somatostatin receptor staining were measured. For the cell line, AIP and ZAC1 (zinc finger regulator of apoptosis and cell cycle arrest) expression, metabolic activity, and clone formation were measured.


RESULTS
Lanreotide pretreatment reduced GH and IGF-I levels and tumor volume (all P < 0.0001). AIP immunostaining was stronger in the lanreotide-pretreated group vs. the surgery-only group (P < 0.001). After lanreotide pretreatment, the AIP score correlated to IGF-I changes in females (R = 0.68, P < 0.05). Somatostatin receptor staining was not reduced in samples with AIP mutations. In GH3 cells, 1 nm octreotide increased AIP mRNA and protein (both P < 0.01) and ZAC1 mRNA expression (P < 0.05). Overexpression of wild-type (but not mutant) AIP increased ZAC1 mRNA expression, whereas AIP siRNA knockdown reduced ZAC1 mRNA (both P < 0.05). The siRNA-mediated knockdown of AIP led to an increased metabolic activity and clonogenic ability of GH3 cells compared with cells transfected with a nontargeting control (both P < 0.001).


CONCLUSIONS
These results suggest that AIP may play a role in the mechanism of action of somatostatin analogs via ZAC1 in sporadic somatotroph tumors and may explain their lack of effectiveness in patients with AIP mutations.
Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
Harvinder S
HS
Chahal
Giampaolo
G
Trivellin
Chrysanthia A
CA
Leontiou
Neda
N
Alband
Robert C
RC
Fowkes
Asil
A
Tahir
Susana C
SC
Igreja
J Paul
JP
Chapple
Susan
S
Jordan
Amelie
A
Lupp
Stefan
S
Schulz
Olaf
O
Ansorge
Niki
N
Karavitaki
Eivind
E
Carlsen
John A H
JA
Wass
Ashley B
AB
Grossman
Márta
M
Korbonits
D000236:Adenoma / Q000188:drug therapy*; D000818:Animals; D018797:Cell Cycle Proteins / Q000032:analysis / Q000502:physiology*; D045744:Cell Line, Tumor; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000188:drug therapy*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000502:physiology*; D051381:Rats; D017481:Receptors, Somatostatin / Q000032:analysis; D015398:Signal Transduction; D013004:Somatostatin / Q000031:analogs & derivatives*; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000502:physiology*
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C106464:PLAGL1 protein, human; D017481:Receptors, Somatostatin; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D013004:Somatostatin