Somatostatin analogs regulate tumor corticotrophs growth by reducing ERK1/2 activity

Donatella Treppiedi, Elena Giardino, Rosa Catalano, Federica Mangili, Pietro Vercesi, Elisa Sala, Marco Locatelli, Maura Arosio, Anna Spada, Giovanna Mantovani, Erika Peverelli

Research output: Contribution to journalArticle

Abstract

Pasireotide has been associated with tumor shrinkage in patients with Cushing's disease subjected to long term treatment. However, to date the implicated molecular mechanisms are poorly elucidated. Here, we tested pasireotide-mediated cytostatic and cytotoxic effects in ACTH-secreting primary tumor cultures and murine corticotroph tumor cell line, AtT-20 cells. We found somatostatin receptor type 5 (SST5) expressed in 17 different ACTH-secreting tumors and SST2 detectable in 15 out of the 17 tissues. Pasireotide caused a slight but significant in vitro inhibition of cell growth in 3 out of 6 ACTH-secreting primary cultures (−12.1 ± 4.3%, P < 0.01 at 10 nM), remarkably reduced phospho-ERK1/2 levels in 5 out of 8 samples (−36.4 ± 20.5%, P < 0.01 at 1 μM) and triggered an increase of caspase 3/7 activity in 2 of 4 tumors (17 ± 3.6%, P < 0.05 at 1 μM). Accordingly, in AtT-20 cells, pasireotide significantly inhibited cell proliferation (−10.5 ± 7.7% at 10 nM, P < 0.05; −13.9 ± 10.9% at 100 nM, P < 0.05; −26.8 ± 8.9% at 1 μM, P < 0.01). Similar antiproliferative actions were exerted by BIM23206 and BIM23120 (SST5&2 selective ligands, respectively), whereas octreotide was effective when used at 1 μM (−13.3 ± 9.1%, P < 0.05). Moreover, a reduction of phospho-ERK1/2 was observed upon pasireotide and BIM23206 treatment (−8.4 ± 28.6%, P < 0.01 and −51.4 ± 15.9%, P < 0.001 at 10 nM, respectively) but not after octreotide and BIM23120 incubation. Finally, pasireotide was able to induce cell apoptosis in AtT-20 cells at lower concentration than octreotide. Altogether these data indicate a downstream implication of SST5-mediated phospho-ERK1/2 inhibition by pasireotide resulting in ACTH-secreting tumor cells proliferation reduction. Moreover, we describe for the first time a pro-apoptotic effect of pasireotide in corticotrophs.

Original languageEnglish
Pages (from-to)31-38
Number of pages8
JournalMolecular and Cellular Endocrinology
Volume483
DOIs
Publication statusPublished - Mar 1 2019

Fingerprint

Corticotrophs
Somatostatin
Tumors
Growth
Adrenocorticotropic Hormone
Octreotide
Neoplasms
Cell proliferation
Cell Proliferation
Caspase 7
Pituitary ACTH Hypersecretion
pasireotide
Cytostatic Agents
Cell growth
Tumor Cell Line
Cell culture
Caspase 3
Cells
Tissue
Apoptosis

Keywords

  • Cell proliferation
  • Corticotrophs
  • ERK1/2
  • Somatostatin analogs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

Somatostatin analogs regulate tumor corticotrophs growth by reducing ERK1/2 activity. / Treppiedi, Donatella; Giardino, Elena; Catalano, Rosa; Mangili, Federica; Vercesi, Pietro; Sala, Elisa; Locatelli, Marco; Arosio, Maura; Spada, Anna; Mantovani, Giovanna; Peverelli, Erika.

In: Molecular and Cellular Endocrinology, Vol. 483, 01.03.2019, p. 31-38.

Research output: Contribution to journalArticle

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abstract = "Pasireotide has been associated with tumor shrinkage in patients with Cushing's disease subjected to long term treatment. However, to date the implicated molecular mechanisms are poorly elucidated. Here, we tested pasireotide-mediated cytostatic and cytotoxic effects in ACTH-secreting primary tumor cultures and murine corticotroph tumor cell line, AtT-20 cells. We found somatostatin receptor type 5 (SST5) expressed in 17 different ACTH-secreting tumors and SST2 detectable in 15 out of the 17 tissues. Pasireotide caused a slight but significant in vitro inhibition of cell growth in 3 out of 6 ACTH-secreting primary cultures (−12.1 ± 4.3{\%}, P < 0.01 at 10 nM), remarkably reduced phospho-ERK1/2 levels in 5 out of 8 samples (−36.4 ± 20.5{\%}, P < 0.01 at 1 μM) and triggered an increase of caspase 3/7 activity in 2 of 4 tumors (17 ± 3.6{\%}, P < 0.05 at 1 μM). Accordingly, in AtT-20 cells, pasireotide significantly inhibited cell proliferation (−10.5 ± 7.7{\%} at 10 nM, P < 0.05; −13.9 ± 10.9{\%} at 100 nM, P < 0.05; −26.8 ± 8.9{\%} at 1 μM, P < 0.01). Similar antiproliferative actions were exerted by BIM23206 and BIM23120 (SST5&2 selective ligands, respectively), whereas octreotide was effective when used at 1 μM (−13.3 ± 9.1{\%}, P < 0.05). Moreover, a reduction of phospho-ERK1/2 was observed upon pasireotide and BIM23206 treatment (−8.4 ± 28.6{\%}, P < 0.01 and −51.4 ± 15.9{\%}, P < 0.001 at 10 nM, respectively) but not after octreotide and BIM23120 incubation. Finally, pasireotide was able to induce cell apoptosis in AtT-20 cells at lower concentration than octreotide. Altogether these data indicate a downstream implication of SST5-mediated phospho-ERK1/2 inhibition by pasireotide resulting in ACTH-secreting tumor cells proliferation reduction. Moreover, we describe for the first time a pro-apoptotic effect of pasireotide in corticotrophs.",
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T1 - Somatostatin analogs regulate tumor corticotrophs growth by reducing ERK1/2 activity

AU - Treppiedi, Donatella

AU - Giardino, Elena

AU - Catalano, Rosa

AU - Mangili, Federica

AU - Vercesi, Pietro

AU - Sala, Elisa

AU - Locatelli, Marco

AU - Arosio, Maura

AU - Spada, Anna

AU - Mantovani, Giovanna

AU - Peverelli, Erika

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N2 - Pasireotide has been associated with tumor shrinkage in patients with Cushing's disease subjected to long term treatment. However, to date the implicated molecular mechanisms are poorly elucidated. Here, we tested pasireotide-mediated cytostatic and cytotoxic effects in ACTH-secreting primary tumor cultures and murine corticotroph tumor cell line, AtT-20 cells. We found somatostatin receptor type 5 (SST5) expressed in 17 different ACTH-secreting tumors and SST2 detectable in 15 out of the 17 tissues. Pasireotide caused a slight but significant in vitro inhibition of cell growth in 3 out of 6 ACTH-secreting primary cultures (−12.1 ± 4.3%, P < 0.01 at 10 nM), remarkably reduced phospho-ERK1/2 levels in 5 out of 8 samples (−36.4 ± 20.5%, P < 0.01 at 1 μM) and triggered an increase of caspase 3/7 activity in 2 of 4 tumors (17 ± 3.6%, P < 0.05 at 1 μM). Accordingly, in AtT-20 cells, pasireotide significantly inhibited cell proliferation (−10.5 ± 7.7% at 10 nM, P < 0.05; −13.9 ± 10.9% at 100 nM, P < 0.05; −26.8 ± 8.9% at 1 μM, P < 0.01). Similar antiproliferative actions were exerted by BIM23206 and BIM23120 (SST5&2 selective ligands, respectively), whereas octreotide was effective when used at 1 μM (−13.3 ± 9.1%, P < 0.05). Moreover, a reduction of phospho-ERK1/2 was observed upon pasireotide and BIM23206 treatment (−8.4 ± 28.6%, P < 0.01 and −51.4 ± 15.9%, P < 0.001 at 10 nM, respectively) but not after octreotide and BIM23120 incubation. Finally, pasireotide was able to induce cell apoptosis in AtT-20 cells at lower concentration than octreotide. Altogether these data indicate a downstream implication of SST5-mediated phospho-ERK1/2 inhibition by pasireotide resulting in ACTH-secreting tumor cells proliferation reduction. Moreover, we describe for the first time a pro-apoptotic effect of pasireotide in corticotrophs.

AB - Pasireotide has been associated with tumor shrinkage in patients with Cushing's disease subjected to long term treatment. However, to date the implicated molecular mechanisms are poorly elucidated. Here, we tested pasireotide-mediated cytostatic and cytotoxic effects in ACTH-secreting primary tumor cultures and murine corticotroph tumor cell line, AtT-20 cells. We found somatostatin receptor type 5 (SST5) expressed in 17 different ACTH-secreting tumors and SST2 detectable in 15 out of the 17 tissues. Pasireotide caused a slight but significant in vitro inhibition of cell growth in 3 out of 6 ACTH-secreting primary cultures (−12.1 ± 4.3%, P < 0.01 at 10 nM), remarkably reduced phospho-ERK1/2 levels in 5 out of 8 samples (−36.4 ± 20.5%, P < 0.01 at 1 μM) and triggered an increase of caspase 3/7 activity in 2 of 4 tumors (17 ± 3.6%, P < 0.05 at 1 μM). Accordingly, in AtT-20 cells, pasireotide significantly inhibited cell proliferation (−10.5 ± 7.7% at 10 nM, P < 0.05; −13.9 ± 10.9% at 100 nM, P < 0.05; −26.8 ± 8.9% at 1 μM, P < 0.01). Similar antiproliferative actions were exerted by BIM23206 and BIM23120 (SST5&2 selective ligands, respectively), whereas octreotide was effective when used at 1 μM (−13.3 ± 9.1%, P < 0.05). Moreover, a reduction of phospho-ERK1/2 was observed upon pasireotide and BIM23206 treatment (−8.4 ± 28.6%, P < 0.01 and −51.4 ± 15.9%, P < 0.001 at 10 nM, respectively) but not after octreotide and BIM23120 incubation. Finally, pasireotide was able to induce cell apoptosis in AtT-20 cells at lower concentration than octreotide. Altogether these data indicate a downstream implication of SST5-mediated phospho-ERK1/2 inhibition by pasireotide resulting in ACTH-secreting tumor cells proliferation reduction. Moreover, we describe for the first time a pro-apoptotic effect of pasireotide in corticotrophs.

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