ECE2022 Poster Presentations Pituitary and Neuroendocrinology (127 abstracts)
Impact of USP8 mutations on corticotroph tumor cells responsiveness to pasireotide
Erika Peverelli 1 , Giusy Marra 1 , Donatella Treppiedi 1 , Genesio Di Muro 1,2 , Emanuela Esposito 1 , Anna Maria Barbieri 1 , Rosa Catalano 1 , Federica Mangili 1 , Marco Locatelli 3,4 , Andrea Lania 5,6 , Emanuele Ferrante 7 , Rita Indirli 1,7 , Anna Spada 1 , Maura Arosio 1,7 & Giovanna Mantovani 1,7
1University of Milan, Department of Clinical Sciences and Community Health, Milano, Italy; 2University Sapienza of Rome, PhD Program in Endocrinological Sciences, Roma, Italy; 3Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy; 4University of Milan, Department of Pathophysiology and Transplantation, Milan, Italy; 5Humanitas Clinical and Research Center, IRCCS, Endocrinology, Diabetology and Medical Andrology Unit, Rozzano, Italy; 6Humanitas University, Department of Biomedical Sciences, Milan, Italy; 7Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy
Somatic mutations in the ubiquitin specific peptidase 8 (USP8) gene have been associated with higher levels of somatostatin (SS) receptor subtype 5 (SSTR5) in adrenocorticotroph hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs). However, a correlation between the USP8 mutational status and favorable responses to pasireotide, the somatostatin multi-receptor ligand acting especially on SSTR5, has not been investigated yet. Here, we studied the impact of USP8 mutations on pasireotide responsiveness in human and murine corticotroph tumor cells. SSTR5 upregulation was observed in USP8-mutated tumors and in USP8 wild-type primary tumor cells transfected with S718del USP8 mutant. However, cell transfection with S718del USP8 and C40-USP8 mutants in in vitro sensitive cultures from USP8 wild-type tumors abolished their ability to respond to pasireotide and did not confer pasireotide responsiveness to the in vitro resistant culture. Pasireotide failed to reduce ACTH secretion in primary cells from one S718P USP8-mutated tumor but exerted a strong antisecretory effect in primary cells from one P720R USP8-mutated tumor. In agreement, AtT-20 cells transfection with USP8 mutants led to SSTR5 expression increase but pasireotide could reduce ACTH production and cyclin E expression in P720R USP8 overexpressing cells, only. In situ Proximity Ligation Assay and immunoflurescence experiments revealed that P720R USP8 mutant is still able to bind 14-3-3 proteins in AtT-20 cells without affecting SSTR5 localization. In conclusion, P720R USP8 mutation might be considered as a molecular predictor of favorable response to pasireotide in corticotroph tumor cells.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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