ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P659

Ligand-dependent internalization of somatostatin receptors

Harmke H van Vugt, Herbert A Schmid & Andreas W Sailer

Novartis Institutes for BioMedical Research, Basel, Switzerland.

Somatostatin (somatotrophin release inhibiting factor; SRIF) is produced primarily in the hypothalamus and pancreas and inhibits the secretion of many hormones and neurotransmitters. Moreover, SRIF and SRIF analogs are able to inhibit tumor growth. Many human neuroendocrine and non-neuroendocrine tumors express the five known somatostatin receptors (sst1–5) in different amounts.

Tachyphylaxis after prolonged treatment with octreotide (Sandostatin) is a well known clinical problem in patients with GEP-NET tumors. Pasireotide (SOM230), which activates sst1,2,3, and 5, in contrast to octreotide which activates sst2 primarily, showed only little tachyphylaxis of hormone secretion in preclinical assays. In order to understand the mechanism underlying receptor activation and tachyphylaxis, we studied somatostatin receptor subtype trafficking and function.

In HEK293 cells stably expressing recombinant human sst2, we found that octreotide, but not pasireotide (1 μM), caused a rapid (within 5 min) and complete internalization of these receptors from the cell membrane to the cytoplasm. Complete recycling of the receptors to the cell membrane was observed after 5 h. Interestingly, both compounds were similarly effective in inhibiting forskolin-induced cAMP production (up to 60% inhibition after 15 min at a 1 μM dose) in these cells. Subsequently we extended our study to the human hepatocellular carcinoma cell line HuH7. Using immunohistochemistry on these cells we detected sst3, 4 and 5, but no sst1 and sst2. Pasireotide was able to significantly inhibit cAMP production (40% inhibition at 1 μM), whereas octreotide was not effective. Preliminary confocal studies showed that pasireotide had no significant effect on sst3 or sst5 localization in HuH7 cells.

These data provide the first information on the specific effects that octreotide and pasireotide exert on the different sst subtypes and give insight in the molecular properties of these two compounds concerning the induction of tachyphylaxis.

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