Endocrine Abstracts (2015) 37 EP170 | DOI: 10.1530/endoabs.37.EP170

Influence of mTOR and ERK 1/2 pathways on the IGF1 negative feedback in GH secreting pituitary adenoma cell line

Carmelina Di Pasquale1, Mariaenrica Bellio1, Erica Gentilin1,2, Teresa Gagliano1, Simona Falletta1, Katiuscia Benfini1, Maria Rosaria Ambrosio1, Ettore degli Uberti1,2 & Maria Chiara Zatelli1,2

1Section of Endocrinology and Internal Medicine, Department of Medical Science, University of Ferrara, Italy, Ferrara, Italy; 2LTTA, laboratorio per le tecnologie delle terapie avanzate, Ferrara, Italy.

Background: Gigantism and acromegaly are the main consequences of GH excess, mainly due to a pituitary adenoma. Surgery is the first therapeutic option, but also medical therapy is employed, being mostly represented by somatostatin analogues (SSA), that reduce both tumour mass and GH hypersecretion. However about 10% of patients is resistant to SSA.

PI3K/Akt/mTOR pathway, activated by growth-factors such as IGF1, is important in regulating many cellular processes.

Aim: To understand whether PI3K/Akt/mTOR and ERK 1/2 pathway can influence IGF1 feed-back in GH secreting pituitary adenoma cell lines, we employed three inhibitors: everolimus (mTOR inhibitor), NVP-BEZ235 (mTOR and PI3K inhibitor) and SCH772984 (ERK 1/2 inhibitor), evaluating their effects in presence or in absence of IGF1.

Materials and methods: Cell viability and GH secretion assays have been performed in the GH3 cell line (rat GH-secreting pituitary adenoma cell line).

Results: IGF1 induced cell viability by 30%. Everolimus significantly reduced viability up to 30%, and this effect was not counteracted by IGF1. NVP-BEZ235 reduced cell viability and IGF1 counteracted this effect, suggesting that this compound could act, at least in part, on IGF1 activated pathways. GH secretion was reduced by IGF1 (40%); Everolimus and NVP-BEZ235 did not significantly affect GH secretion and these compounds did not enhance the negative feed-back of IGF1 on GH secretion. SCH772984 did not influence viability but reduced GH secretion up to 20% without enhancing IGF1 negative feed-back. Moreover, Everolimus and NVP-BEZ235 did not influence SCH772984 effects.

Conclusions: These data indicate that IGF1 is important in regulating proliferation and GH secretion in GH3 cells. mTOR blockade reduce viability without affecting GH secretion. ERK 1/2 affects secretion but not IGF1 negative feed-back. In conclusion, our data suggest that mTOR and ERK 1/2 pathways are not involved in IGF1 feed-back on GH secretion.