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Endocrine Abstracts (2016) 41 EP865 | DOI: 10.1530/endoabs.41.EP865

Department Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.


Acromegaly results from excess growth hormone (GH) secretion, due to a pituitary adenoma. Surgery is the first option recommended for treatment of GH secreting pituitary adenomas; medical therapy, mostly represented by somatostatin analogues (SSA), is most often used if surgery is not successful. Insulin-like Growth Factor-1 (IGF-1) physiologically reduces GH levels through an endocrine negative feedback loop. IGF-1 exerts its effects also through PI3K/Akt/mTOR pathway activation and regulates different cellular processes.

The aim of this study is to understand whether PI3K/Akt/mTOR pathway can influence IGF-1 feed-back in a rat pituitary adenoma cell line (GH3 cells). We used three inhibitors: Everolimus (mTOR inhibitor), NVP-BEZ235 (mTOR and PI3K inhibitor) and LY294002 (PI3K inhibitor) in the presence or in the absence of IGF-1. We evaluated cell viability by ATPlite Assay, GH secretion by ELISA and Akt phosphorylation by Western blot.

We found that cell viability was induced by IGF-1 (+30%) and reduced by Everolimus up to 30%; this effect was not counteracted by IGF-1. NVP-BEZ235 reduced cell viability and IGF-1 counteracted this effect. GH secretion was reduced by IGF-1 (40%); this effect was not affected by Everolimus, but was blocked by NVP-BEZ235. Moreover, IGF-1 induced Akt phosphorylation, that was enhanced by Everolimus and completely abolished by NVP-BEZ235. To validate these results, we assessed LY294002 alone and with IGF-1, confirming that IGF1 increases Akt phosphorylation while LY294002 arrest this effect.

These results show that IGF-1 is an important regulator of cell proliferation and GH secretion in pituitary cells and that PI3K/Akt/mTOR inhibitors may modulate IGF-1 signaling. This pathway has a role in IGF-1 negative feedback on GH secretion, through Akt inhibition. Therefore, mTOR pathway may represent a possible target for treatment of GH-secreting pituitary adenomas.

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