Cytotoxic Effect of Progesterone, Tamoxifen and Their Combination in Experimental Cell Models of Human Adrenocortical Cancer

• Published in: Frontiers in endocrinology (Lausanne) Vol. 12; p. 669426
• Main Authors: Rossini, Elisa, Tamburello, Mariangela, Abate, Andrea, Beretta, Silvia, Fragni, Martina, Cominelli, Manuela, Cosentini, Deborah, Hantel, Constanze, Bono, Federica, Grisanti, Salvatore, Poliani, Pietro Luigi, Tiberio, Guido A M, Memo, Maurizio, Sigala, Sandra, Berruti, Alfredo
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 26.04.2021
• Subjects: ACC cell lines; ACC primary cells; Adrenal Cortex Neoplasms - drug therapy; Adrenal Cortex Neoplasms - metabolism; Adrenal Cortex Neoplasms - pathology; adrenocortical carcinoma; Adrenocortical Carcinoma - drug therapy; Adrenocortical Carcinoma - metabolism; Adrenocortical Carcinoma - pathology; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis; Cell Proliferation; Drug Therapy, Combination; Endocrinology; estrogen receptors; Female; Humans; Male; Progesterone - pharmacology; progesterone receptors; Progestins - pharmacology; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; tamoxifen; Tamoxifen - pharmacology; Tumor Cells, Cultured; adrenocortical carcinoma; ACC cell lines; ACC primary cells; estrogen receptors; tamoxifen; progesterone receptors
• ISSN: 1664-2392; 1664-2392
• DOI: 10.3389/fendo.2021.669426

Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER- over the ER- .Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER- / signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC : MUC-1 cells: 67.58 µM (95%CI: 63.22-73.04), ACC115m cells: 51.76 µM (95%CI: 46.45-57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC : 5.43 µM (95%CI: 5.18-5.69 µM) mainly involving ER- , as their nuclear localization increased after tamoxifen: Δ A.U. treated untreated: 12 h: +27.04% (p < 0.01); 24 h: +36.46% (p < 0.0001). This effect involved the SF-1 protein reduction: Pg: -36.34 ± 9.26%; tamoxifen: -46.25 ± 15.68% (p < 0.01). Finally, in a cohort of 36 ACC samples, immunohistochemistry showed undetectable/low level of ERs, while PgR demonstrated a higher expression. In conclusion, ACC experimental cell models expressed PgR and low levels of ER in line with data obtained in patient tissues, thus limiting the possibility of a clinical approach targeting ER. Interestingly, Pg exerted cytotoxicity also in metastatic ACC cells, although with low potency.