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Statins Directly Regulate Pituitary Cell Function and Exert Antitumor Effects in Pituitary Tumors.

Abstract：

INTRODUCTION:Pituitary neuroendocrine tumors (PitNETs), the most abundant of all intracranial tumors, entail severe comorbidities. First-line therapy is transsphenoidal surgery, but subsequent pharmacological therapy is often required. Unfortunately, many patients are/become unresponsive to available drugs (somatostatin analogues [SSAs]/dopamine agonists), underscoring the need for new therapies. Statins are well-known drugs commonly prescribed to treat hyperlipidemia/cardiovascular diseases, but can convey additional beneficial effects, including antitumor actions. The direct effects of statins on normal human pituitary or PitNETs are poorly known. Thus, we aimed to explore the direct effects of statins, especially simvastatin, on key functional parameters in normal and tumoral pituitary cells, and to evaluate the combined effects of simvastatin with metformin (MF) or SSAs. METHODS:Effects of statins in cell proliferation/viability, hormone secretion, and signaling pathways were evaluated in normal pituitary cells from a primate model (Papio anubis), tumor cells from corticotropinomas, somatotropinomas, nonfunctioning pituitary tumors, and PitNET cell-lines (AtT20/GH3-cells). RESULTS:All statins decreased AtT20-cell proliferation, simvastatin showing stronger effects. Indeed, simvastatin reduced cell viability and/or hormone secretion in all PitNETs subtypes and cell-lines, and ACTH/GH/PRL/FSH/LH secretion (but not expression), in primate cell cultures, by modulating MAPK/PI3K/mTOR pathways and expression of key receptors (GH-releasing hormone-receptor/ghrelin-R/Kiss1-R) regulating pituitary function. Addition of MF or SSAs did not enhance simvastatin antitumor effects. CONCLUSION:Our data reveal direct antitumor effects of simvastatin on PitNET-cells, paving the way to explore these compounds as a possible tool to treat PitNETs.

journal_name

Neuroendocrinology

journal_title

Neuroendocrinology

authors

Vázquez-Borrego MC,Fuentes-Fayos AC,Herrera-Martínez AD,Venegas-Moreno E,L-López F,Fanciulli A,Moreno-Moreno P,Alhambra-Expósito MR,Barrera-Martín A,Dios E,Blanco-Acevedo C,Solivera J,Granata R,Kineman RD,Gahete MD,Soto-Mor

doi

10.1159/000505923

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

1028-1041

issue

11-12

eissn

0028-3835

issn

1423-0194

pii

000505923

journal_volume

110

pub_type

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Statins Directly Regulate Pituitary Cell Function and Exert Antitumor Effects in Pituitary Tumors.