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Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
Published on: November 5, 2014
Somatostatin analogs regulate tumor corticotrophs growth by reducing ERK1/2 activity
Donatella Treppiedi1, Elena Giardino1, Rosa Catalano2
1Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrine Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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.
Insights
Pasireotide inhibits ACTH-secreting tumor cell proliferation and induces apoptosis, primarily through somatostatin receptor type 5 (SST5) and phospho-ERK1/2 pathway inhibition. This study elucidates molecular mechanisms behind pasireotide
Area of Science:
- Endocrinology and Molecular Oncology
- Investigating the molecular mechanisms of endocrine tumors
Background:
- Pasireotide demonstrates tumor shrinkage in Cushing's disease patients.
- The precise molecular mechanisms underlying pasireotide's efficacy remain poorly understood.
- ACTH-secreting tumors, including corticotroph tumors, are the focus of this investigation.
Purpose of the Study:
- To investigate the cytostatic and cytotoxic effects of pasireotide on ACTH-secreting tumor cells.
- To elucidate the molecular pathways, particularly somatostatin receptor (SST) involvement, mediating pasireotide's action.
- To explore the impact of pasireotide on cell proliferation, signaling pathways (phospho-ERK1/2), and apoptosis in corticotroph tumor models.
Main Methods:
- Assessed somatostatin receptor type 5 (SST5) and SST2 expression in primary ACTH-secreting tumor tissues.
- Evaluated in vitro effects of pasireotide, BIM23206, BIM23120, and octreotide on cell growth and proliferation in primary cultures and AtT-20 cells.
- Measured phospho-ERK1/2 levels and caspase 3/7 activity following treatment with pasireotide and other somatostatin analogs.
Main Results:
- SST5 was detected in 17/17 ACTH-secreting tumors, and SST2 in 15/17.
- Pasireotide significantly inhibited cell growth and proliferation in primary cultures and AtT-20 cells, with notable reduction in phospho-ERK1/2 levels.
- Pasireotide induced apoptosis in AtT-20 cells at lower concentrations than octreotide, suggesting a distinct pro-apoptotic effect.
Conclusions:
- Pasireotide's anti-proliferative effect on ACTH-secreting tumor cells is mediated by SST5-dependent inhibition of phospho-ERK1/2 signaling.
- Pasireotide exhibits a pro-apoptotic effect in corticotroph tumor cells, a novel finding for this agent.
- These findings provide crucial insights into the molecular mechanisms of pasireotide, supporting its therapeutic potential in ACTH-secreting pituitary tumors.
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