-
- Donatella Treppiedi
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Genesio Di Muro
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Giusy Marra
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Anna Maria Barbieri
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Federica Mangili
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Rosa Catalano
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Andreea Serban
- 2Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy
-
- Emanuele Ferrante
- 2Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy
-
- Marco Locatelli
- 3Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
-
- Andrea G Lania
- 5Humanitas Clinical and Research Center IRCCS, Endocrinology, Diabetology and Medical Andrology Unit, Milan, Italy
-
- Maura Arosio
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Anna Spada
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Erika Peverelli
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
-
- Giovanna Mantovani
- 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
抄録
<jats:p>Cushing’s disease (CD) is a rare endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor. Pasireotide is the only pituitary-targeted drug approved for adult patients. Nevertheless, many side effects are encountered and curative therapy is still challenging. Ubiquitin-specific peptidase 8 (USP8) plays a crucial role in the modulation of corticotroph cells growth and ACTH secretion. Here, we explored the anticancer potential of the USP8 inhibitor RA-9 in USP8-WT human tumor corticotroph cells and murine AtT-20 cells. Our results showed that RA-9 causes cell proliferation decrease (−24.3 ± 5.2%, <jats:italic>P</jats:italic> < 0.01) and cell apoptosis increase (207.4 ± 75.3%, <jats:italic>P</jats:italic> < 0.05) in AtT-20 cells, as observed with pasireotide. Moreover, RA-9 reduced ACTH secretion in AtT-20 cells (−34.1 ± 19.5%, <jats:italic>P</jats:italic> < 0.01), as well as in AtT-20 cells transfected with USP8 mutants, and in one out of two primary cultures <jats:italic>in vitro</jats:italic> responsive to pasireotide (−40.3 ± 6%). An RA-9 mediated decrease of pERK1/2 levels was observed in AtT-20 cells (−52.3 ± 13.4%, <jats:italic>P</jats:italic> < 0.001), comparable to pasireotide, and in primary cultures, regardless of their<jats:italic> in vitro</jats:italic> responsiveness to pasireotide. Upregulation of p27 was detected upon RA-9 treatment only, both in AtT-20 cells (167.1 ± 36.7%, <jats:italic>P</jats:italic> < 0.05) and in one primary culture tested (168.4%), whilst pCREB level was similarly halved in AtT-20 cells by both RA-9 and pasireotide. Altogether, our data demonstrate that RA-9 is efficient in exerting cytotoxic effects and inhibitory actions on cell proliferation and hormone secretion by modulating the expression of pERK1/2, pCREB and p27. Inhibition of USP8 might represent a novel strategy to target both USP8-WT and USP8-mutated tumors in CD patients.</jats:p>
収録刊行物
-
- Endocrine-Related Cancer
-
Endocrine-Related Cancer 28 (8), 573-582, 2021-08-01
Bioscientifica