Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

Erika Hubina, Alexandra M. Nanzer, Matthew R. Hanson, Enrica Ciccarelli, Marco Losa, Daniela Gaia, Mauro Papotti, Maria Rosaria Terreni, Sahira Khalaf, Suzanne Jordan, S. Czirják, Z. Hanzély, György M. Nagy, M. Góth, Ashley B. Grossman, Márta Korbonits

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Abstract

Objectives: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. Methods: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. Results: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK 1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. Conclusions: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

Original languageEnglish
Pages (from-to)371-379
Number of pages9
JournalEuropean Journal of Endocrinology
Volume155
Issue number2
DOIs
Publication statusPublished - Aug 2006

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Pituitary Neoplasms
Somatostatin
Phosphotransferases
Octreotide
Up-Regulation
Down-Regulation
Growth Hormone-Secreting Pituitary Adenoma
Cyclin-Dependent Kinase Inhibitor p27
Neoplasms
Therapeutics
Cell Cycle Checkpoints
Immunoblotting
Thymidine
Proteins
Cell Proliferation
Cell Line
Growth

ASJC Scopus subject areas

  • Endocrinology

Cite this

Hubina, E., Nanzer, A. M., Hanson, M. R., Ciccarelli, E., Losa, M., Gaia, D., ... Korbonits, M. (2006). Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. European Journal of Endocrinology, 155(2), 371-379. https://doi.org/10.1530/eje.1.02213

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. / Hubina, Erika; Nanzer, Alexandra M.; Hanson, Matthew R.; Ciccarelli, Enrica; Losa, Marco; Gaia, Daniela; Papotti, Mauro; Terreni, Maria Rosaria; Khalaf, Sahira; Jordan, Suzanne; Czirják, S.; Hanzély, Z.; Nagy, György M.; Góth, M.; Grossman, Ashley B.; Korbonits, Márta.

In: European Journal of Endocrinology, Vol. 155, No. 2, 08.2006, p. 371-379.

Research output: Contribution to journalArticle

Hubina, E, Nanzer, AM, Hanson, MR, Ciccarelli, E, Losa, M, Gaia, D, Papotti, M, Terreni, MR, Khalaf, S, Jordan, S, Czirják, S, Hanzély, Z, Nagy, GM, Góth, M, Grossman, AB & Korbonits, M 2006, 'Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours', European Journal of Endocrinology, vol. 155, no. 2, pp. 371-379. https://doi.org/10.1530/eje.1.02213
Hubina, Erika ; Nanzer, Alexandra M. ; Hanson, Matthew R. ; Ciccarelli, Enrica ; Losa, Marco ; Gaia, Daniela ; Papotti, Mauro ; Terreni, Maria Rosaria ; Khalaf, Sahira ; Jordan, Suzanne ; Czirják, S. ; Hanzély, Z. ; Nagy, György M. ; Góth, M. ; Grossman, Ashley B. ; Korbonits, Márta. / Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. In: European Journal of Endocrinology. 2006 ; Vol. 155, No. 2. pp. 371-379.
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abstract = "Objectives: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. Methods: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. Results: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK 1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. Conclusions: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.",
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T1 - Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

AU - Hubina, Erika

AU - Nanzer, Alexandra M.

AU - Hanson, Matthew R.

AU - Ciccarelli, Enrica

AU - Losa, Marco

AU - Gaia, Daniela

AU - Papotti, Mauro

AU - Terreni, Maria Rosaria

AU - Khalaf, Sahira

AU - Jordan, Suzanne

AU - Czirják, S.

AU - Hanzély, Z.

AU - Nagy, György M.

AU - Góth, M.

AU - Grossman, Ashley B.

AU - Korbonits, Márta

PY - 2006/8

Y1 - 2006/8

N2 - Objectives: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. Methods: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. Results: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK 1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. Conclusions: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

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