A potential inhibitory role for the new truncated variant of somatostatin receptor 5, sst5TMD4, in pituitary adenomas poorly responsive to somatostatin analogs.
BACKGROUND
Somatostatin (SST) receptors, specially sst2 and sst5, provide a valuable target to inhibit excessive hormone release and cell growth in pituitary tumors by using SST analogs (SSAs). Unfortunately, an appreciable proportion of tumors fail to respond to SSA despite expressing high levels of one or more ssts. Recently we identified two novel truncated sst5 variants, sst5TMD5, and sst5TMD4, absent in normal pituitary but expressed in pituitary tumors.


OBJECTIVE
We aimed at exploring the potential role of sst5TMD5 and sst5TMD4 in the poor response of some tumors to SSA in vivo and in vitro. Specifically, 25 somatotropinomas showing different responses to octreotide in vivo and sst2 (BIM-23197)- and sst5(BIM-23268)-selective compounds in vitro were screened for sst5TMD5/sst5TMD4 expression by real-time PCR. Relationships between ssts expression and in vivo and in vitro secretory response of the corresponding pituitary samples were assessed.


RESULTS
sst5TMD5 was absent in all samples analyzed. sst5TMD4 was found in 85% of tumors, and its expression was positively correlated to that of sst5 (R(2) = 0.79, P < 0.001). Expression of sst5TMD4 was negatively correlated with the ability of octreotide to reduce GH levels in vivo and partially negatively correlated with inhibition of GH secretion by an sst5 selective agonist (BIM-23268) in vitro.


CONCLUSIONS
These results indicate that sst5TMD4 is related to the reduced ability of octreotide at normalizing hormone secretion in poorly responsive tumors in vivo. Further studies will help to evaluate the potential use of sst5TMD4 expression in surgically removed pituitary adenomas as a predictor of the subsequent response of different pituitary tumors to SSA therapy.
Durán-Prado
Mario
M
Department of Cell Biology, Physiology, and Immunology, University of Córdoba, E-14014 Córdoba, Spain.
Saveanu
Alexandru
A
Luque
Raul M
RM
Gahete
Manuel D
MD
Gracia-Navarro
Francisco
F
Jaquet
Philippe
P
Dufour
Henry
H
Malagón
María M
MM
Culler
Michael D
MD
Barlier
Anne
A
Castaño
Justo P
JP
D000172:Acromegaly / Q000235:genetics; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014644:Genetic Variation; D006801:Humans; D015282:Octreotide / Q000627:therapeutic use; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000235:genetics*; D017384:Sequence Deletion; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
D018931:Antineoplastic Agents, Hormonal; C111784:BIM 23197; C121506:BIM 23268; D009842:Oligopeptides; D010879:Piperazines; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D013004:Somatostatin; C094573:somatostatin receptor 5; D015282:Octreotide