Endocrine Abstracts

As for many tumor types, it has been shown that the Akt pathway is overexpressed and activated in human pituitary tumors. Thus, pituitary tumors may be sensitive to the anti-proliferative effects of mTOR inhibitors. However, part of non-functioning pituitary tumors are rapamycin-resistant. Torin1, second-generation ATP-competitive mTOR kinase inhibitor, suppresses both mTORC1 and mTORC2 complexes. To evaluate the in vitro effects of the mTOR inhibitor Torin1 on pituitary cells, a rat non-secreting pituitary tumor cell line, MtT/E, and human non-functioning pituitary adenoma (NFPA) cells were used.

Treatment of MtT/E cells with Torin1 induced a significant dose- and time-dependent decrease of cell viability and cell number. Incubation of cells from four NFPAs with Torin1 significantly reduced the number of viable cells by 25–45%. The anti-proliferative effects of Torin1 on pituitary tumor cells were found to be mediated by G0/G1 cell cycle arrest associated with cyclin D1 and cyclin D3 suppression, apoptosis reflected by increased fraction of cleaved caspase and subG1 events, and autophagy tested with autophagy markers, LC3 and p62. Torin1 increased p53 levels and p53 inhibitor, pifithrin-alpha, blocked the effects of Torin1 on both cleaved caspase and p62 expression. Expression of phosphorylated-p70S6K and phosphorylated-Akt was significantly reduced by Torin1. Interestingly, the protein expression of the negative regulator of PI3K, the PTEN phosphatase, was significantly decreased by Torin1 in MtT/E cells.

Our results show that Torin1 potently inhibits pituitary cell proliferation suggesting that mTOR inhibitors may be a promising antiproliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors unresponsive to current treatments.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.