The telomerase/shelterin system is impaired in acromegaly and Cushing´s disease: Potential pathophysiological relevance

Pituitary Tumours (PiTs) present significant challenges in diagnosis and treatments due to their heterogeneity, complex pathophysiology and endocrine comorbidities. Current therapies (i.e., surgery/radiotherapy/pharmacological treatment) frequently become ineffective over time, leading to low quality of life and high recurrence rates. Therefore, identifying alternative medical tools for these rare pathologies is crucial. The alteration of the telomerase/shelterin (TEL/SHEL) molecular complexes has been associated with cancer pathophysiology and progression; however, their role in PiTs remains poorly understood. Herein, we uncovered a profound dysregulation in the expression of key components of the TEL/SHEL systems in growth-hormone, adrenocorticotropic-hormone, and prolactin-hormone producing PiTs [GHomas (n = 50)/ACTHomas (n = 19)/PRLomas (n = 6), respectively] versus non-tumour pituitary tissues (n = 10), and identified critical dysregulated components in GHomas, ACTH, and PRLomas, some of them associated with key clinical features in GHomas (i.e., sinus-invasion/visual-alteration/cephalea, etc.). Presurgery treatment is likely not a confounding variable in the alterations observed in the TEL/SHEL system in PiTs. Moreover, we demonstrated that TEL activity inhibition (using BIBR1532) in primary-patient cell-cultures and cell-line models (GH3/AtT-20) might serve as a potential therapeutic tool by reducing cell-proliferation and stem-cell capacity through the modulation of key oncogenic processes, including GH/ACTH synthesis, cell-cycle, and DNA Damage Repair (DDR) pathways. Notably, we also demonstrated that BIBR1532, in combination with somatostatin-analogues, exerted a synergistic/additive anti-proliferative effect in GH3 and AtT-20 cells. Altogether, we demonstrate a profound TEL/SHEL-associated molecular dysregulation in GHomas and ACTHomas, which could serve as a potential source of novel diagnostic/prognostic biomarkers and therapeutic targets, offering a clinically relevant opportunity worth to be explored in humans.