ECE2024 Poster Presentations Adrenal and Cardiovascular Endocrinology (95 abstracts)
Sphingosine kinase 1 inhibitor safingol as a new possible therapeutic strategy for adrenocortical carcinoma
Emma Nozza 1,2 , Rosa Catalano 1 , Emanuela Esposito 1,2 , Serena Palmieri 3 , Barbara Altieri 4 , Laura-Sophie Landwehr 4 , Hantel Constanze 5,6 , Sandra Sigala 7 , Emanuele Ferrante 3 , Giovanna Mantovani 1,3 & Erika Peverelli 1,3
1University of Milan, Department of Clinical Sciences and Community Health, Milan, Italy; 2University of Milan, Phd Program in Experimental Medicine, Milan, Italy; 3Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy; 4University of Würzburg, Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, Würzburg, Germany; 5University Hospital Zurich (USZ) and University of Zurich (UZH), Department of Endocrinology, Diabetology and Clinical Nutrition, Zurich, Switzerland; 6University Hospital Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik III, Dresden, Germany; 7University of Brescia, Section of Pharmacology, Department of Molecular and Translational Medicine, Brescia, Italy
Sphingosine kinase 1 (SphK1) is the enzyme deputed to the phosphorylation of sphingosine in sphingosine-1-phosphate (S1P). S1P promotes ERK phosphorylation with increasing cellular proliferation, AKT phosphorylation, that induces apoptosis resistance and cell migration. It has been recently demonstrated that SphK1 is overexpressed in adrenocortical carcinoma (ACC) in comparison to adenomas (ACA) and that a high expression is related to worse outcome. Different SphK1 inhibitors have been developed to prevent S1P production and induce sphingosine accumulation resulting in cell apoptosis. Among these inhibitors, safingol was used in two phase I clinical trials on solid cancers, also including a small number of ACC patients, where it was clinically active in combination with other chemotherapies. Despite these interesting premises, safingol has never been tested on ACC in vitromodels. Aim of this study was 1) to assess the expression of SphK1 in ACC, ACA, and normal adrenal tissues (NA) and in 4 human ACC cell lines; 2) to test the effect of safingol on cellular viability, proliferation, and apoptosis in different ACC cell models. Western Blot analysis revealed that NA tissues (n=8) displayed the lowest SphK1 level (P<0.001 vs ACC or ACA), while SphK1 expression in ACC (n=8) was 2-fold higher than in ACA (n=8) (P<0.05). Among ACC cell lines, SK showed similarly greater levels in JIL-2266 and MUC-1 compared to H295R and TVBF-7. After 72 h of safingol treatment, all the cell lines displayed a significant reduction of cell viability [H295R safingol 5 μM -52.30 (32.51)%; JIL-2266 safingol 4 μM -51.96 (58.91)%; MUC-1 safingol 3 μM -30.38 (20.90)%; TVBF-7 safingol 8 μM -51.52 (57.50)%]. Cellular proliferation was assessed at the first dosage showing viability reduction, and it was decreased as well (P<0.05) in all cell lines [H295R safingol 5 μM -55.73 (57.52)%; JIL-2266 safingol 4 μM -64.53 (16.55)%; MUC-1 safingol 3 μM -51.53 (24.99)%; TVBF-7 safingol 8 μM -57.36 (35.52)%]. Pro-apoptotic effect of safingol was evaluated via caspases 3 and 7 activity quantification and found significantly increased (P<0.05) after 24 h of treatment [H295R safingol 7.5 μM+146.73 (197.5)%; JIL-2266 safingol 4 μM+141.6 (68.8)%; MUC-1 safingol 5 μM+38.20 (61.6)%; TVBF-7 safingol 8 μM+250.14 (258.6)%].In conclusion, our data demonstrated an overexpression of SphK1 in ACC vs ACA and NA, suggesting that it may represent a novel diagnostic biomarker for ACC. Moreover, our results support the use of SphK1 inhibitor safingol as a novel possible therapeutic strategy for ACC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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