Abstract
Medical treatments for corticotrophinomas are limited, and we therefore investigated the effects of epigenetic modulators, a new class of anti-tumour drugs, on the murine adrenocorticotropic hormone (ACTH)-secreting corticotrophinoma cell line AtT20. We found that AtT20 cells express members of the bromo and extra-terminal (BET) protein family, which bind acetylated histones, and therefore, studied the anti-proliferative and pro-apoptotic effects of two BET inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, using CellTiter Blue and Caspase Glo assays, respectively. JQ1 and PFI-1 significantly decreased proliferation by 95% (P < 0.0005) and 43% (P < 0.0005), respectively, but only JQ1 significantly increased apoptosis by >50-fold (P < 0.0005), when compared to untreated control cells. The anti-proliferative effects of JQ1 and PFI-1 remained for 96 h after removal of the respective compound. JQ1, but not PFI-1, affected the cell cycle, as assessed by propidium iodide staining and flow cytometry, and resulted in a higher number of AtT20 cells in the sub G1 phase. RNA-sequence analysis, which was confirmed by qRT-PCR and Western blot analyses, revealed that JQ1 treatment significantly altered expression of genes involved in apoptosis, such as NFκB, and the somatostatin receptor 2 (SSTR2) anti-proliferative signalling pathway, including SSTR2. JQ1 treatment also significantly reduced transcription and protein expression of the ACTH precursor pro-opiomelanocortin (POMC) and ACTH secretion by AtT20 cells. Thus, JQ1 treatment has anti-proliferative and pro-apoptotic effects on AtT20 cells and reduces ACTH secretion, thereby indicating that BET inhibition may provide a novel approach for treatment of corticotrophinomas.
Highlights
Corticotrophinomas represent >10% of all surgically removed pituitary adenomas, which are the most commonly encountered intracranial neoplasms that are identified in >25% of unselected autopsies and approximately 20% of the population undergoing intracranial imaging (Daly et al 2009)
Our studies have revealed that JQ1 treatment significantly decreased proliferation and increased apoptosis of the adrenocorticotropic hormone (ACTH)-secreting pituitary tumour cells AtT20
Our data indicate that inhibitors of the bromo and extra-terminal (BET) protein family may provide a novel therapeutic strategy for the treatment of ACTH-secreting pituitary neuroendocrine tumours (NETs)
Summary
Corticotrophinomas represent >10% of all surgically removed pituitary adenomas, which are the most commonly encountered intracranial neoplasms that are identified in >25% of unselected autopsies and approximately 20% of the population undergoing intracranial imaging (Daly et al 2009). Pharmacological treatments are available for patients for whom transsphenoidal surgery has not been successful in removing the corticotrophinomas and these include inhibitors of steroidogenesis (e.g. metyraprone, ketoconazole, mitotane, etomidate and osilodrostat); glucocorticoid antagonists (e.g. mifepristone); dopamine agonists such as cabergoline; and somatostain analogues such as pasireotide (Cuevas-Ramos et al 2016). These current medical treatments for corticotrophinomas have limited efficacy, and there is a clinically unmet need for improved pharmacological treatments for corticotrophinomas, especially for those occurring in patients who have contraindications for surgery or have had unsuccessful surgery. In order to determine if BET inhibitors may represent an effective novel therapy for corticotrophinomas in reducing proliferation and increasing apoptosis of these pituitary cells, we first investigated the mouse corticotroph tumour cell line AtT20 for expression of the BET protein family members and the effects of the BET inhibitors JQ1 and PFI-1 on proliferation, apoptosis and ACTH secretion by these pituitary cells
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