Somatostatin analogs currently used in the treatment of
acromegaly and other
neuroendocrine tumors inhibit
hormone secretion and cell proliferation by binding to
somatostatin receptor type (SST) 2 and 5. The antiproliferative pathways coupled to these receptors have been only partially characterized. The aim of this study was to evaluate the effect of
octreotide and super selective SST2 (
BIM23120) and SST5 (
BIM23206) analogs on apoptotic activity and apoptotic gene expression in human somatotroph
tumor cells. Eight somatotroph
tumors expressing similar levels of SST2 and SST5 evaluated by real-time PCR and western blot analyses were included in the study. In cultured cells obtained from these
tumors,
octreotide induced a dose-dependent increase of
caspase-3 activity (160+/-20% vs basal
at 10 nM) and cleaved
cytokeratin 18 levels (172+/-25% vs basal) at concentrations higher than 0.1 nM. This effect was due to SST2 activation since
BIM23120 elicited comparable responses, while
BIM23206 was ineffective. BIM23120-stimulated apoptosis was dependent on
phosphatases, since it was abrogated by the inhibitor
orthovanadate, and independent from the induction of apoptosis-related genes, such as p53, p63, p73, Bcl-2, Bax, BID, BIK, TNFSF8, and FADD. In somatotroph
tumors, both
BIM23120 and BIM2306 caused growth arrest as indicated by the increase in p27 and decrease in
cyclin D1 expression. In conclusion, the present study showed that
octreotide-induced apoptosis in human somatotroph
tumor cells by activating SST2. This effect, together with the
cytostatic action exerted by both SST2 and SST5 analogs, might account for the
tumor shrinkage observed in acromegalic patients treated with long-acting
somatostatin analogs.