Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures

Autor: Mohamed, Amira, Blanchard, Marie-Pierre, Albertelli, Manuela, Barbieri, Federica, Brue, Thierry, Niccoli, Patricia, Delpero, Jean-Robert, Monges, Genevieve, Garcia, Stephane, Ferone, Diego, Florio, Tullio, Enjalbert, Alain, Moutardier, Vincent, Schonbrunn, Agnes, Gerard, Corinne, Barlier, Anne, Saveanu, Alexandru
Přispěvatelé: Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universita degli studi di Genova, Department of Surgical Oncology, Université de la Méditerranée - Aix-Marseille 2, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Departement de chirurgie thoracique et des maladies de l'oesophage [Hôpital Nord - APHM], Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), The University of Texas Health Science Center at Houston (UTHealth), Università degli studi di Genova = University of Genoa (UniGe), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM]
Rok vydání: 2014
Předmět:
Adult
Male
endocrine system
MESH: Neuroendocrine Tumors
Antineoplastic Agents
Hormonal
Cell Survival
MESH: Somatostatin
Apoptosis
MESH: Caspase 7
DNA Fragmentation
Octreotide
Stomach Neoplasms
MESH: Cell Proliferation
MESH: Caspase 3
Intestinal Neoplasms
MESH: Receptors
Somatostatin
Cyclic AMP
Tumor Cells
Cultured
MESH: DNA Fragmentation
Humans
MESH: Tumor Cells
Cultured
Receptors
Somatostatin
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
MESH: Intestinal Neoplasms
MESH: Cyclic AMP
Aged
Cell Proliferation
MESH: Aged
Caspase 7
MESH: Humans
MESH: Middle Aged
MESH: Octreotide
Caspase 3
MESH: Apoptosis
MESH: Adult
MESH: Stomach Neoplasms
MESH: Antineoplastic Agents
Hormonal
Middle Aged
MESH: Male
Pancreatic Neoplasms
Neuroendocrine Tumors
MESH: Cell Survival
Chromogranin A
Female
MESH: Chromogranin A
MESH: Pancreatic Neoplasms
Somatostatin
MESH: Female
Zdroj: Endocrine-Related Cancer
Endocrine-Related Cancer, BioScientifica, 2014, 21 (5), pp.691-704. ⟨10.1530/ERC-14-0086⟩
Endocrine-Related Cancer, 2014, 21 (5), pp.691-704. ⟨10.1530/ERC-14-0086⟩
ISSN: 1479-6821
1351-0088
Popis: International audience; Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.
Databáze: OpenAIRE
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