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D Dworakowska, Centre for Endocrinology, Barts and the London School of Medicine, London, United Kingdom
E Wlodek, Centre for Endocrinology, Barts and the London School of Medicine, London, United Kingdom
C Leontiou, London, United Kingdom
S Igreja, London, United Kingdom
M Cakir, Centre for Endocrinology, Barts and the London School of Medicine, London, United Kingdom
M Teng, London, United Kingdom
N Prodromou, Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, London, United Kingdom
M Goth, 2nd Dept. of Medicine National Health Center, Division of Endocrinology, Budapest, Hungary
S Grozinsky-Glasberg, Endocrine Institute, Beilinson Hospital, Petah Tikva, Israel
M Gueorguiev, London, United Kingdom
B Kola, Endocrinology, William Harvey research Insttute, London, United Kingdom
M Korbonits, Endocrinology, Barts and the London Medical School, London, United Kingdom
A Grossman, Dept. of Endocrinology, St. Bartholomew's Hospital, London, United Kingdom

Correspondence: Dorota Dworakowska, Email: ddw{at}amg.gda.pl

Abstract

Raf/MEK/ERK and PI3K/Akt/mTOR cascades are key signalling pathways interacting with each other to regulate cell growth and tumourigenesis. We have previously shown B-Raf and Akt over-expression and/or over-activation in pituitary adenomas. The aim of this study was to assess the expression of their downstream components (MEK1/2, ERK1/2, mTOR, TSC2, p70S6K) and effectors (c-MYC and CYCLIN D1).

We studied tissue from 16 non-functioning pituitary adenomas (NFPAs), 6 GH-omas,

6 PRL-omas and 6 ACTH-omas, all collected at transsphenoidal surgery; 16 normal autopsy pituitaries were used as controls. The expression of phospho- and total protein was assessed with Western immunoblotting, and the mRNA expression with quantitative RT-PCR.

The expression of pSer217/221 MEK1/2 and pThr183 ERK1/2 (but not total MEK1/2 or ERK1/2) was significantly higher in all tumour sub-types in comparison to normal pituitaries. There was no difference in the expression of phosphorylated/total mTOR, TSC2 or p70S6K between pituitary adenomas and controls. Neither c-MYC phosphorylation at Ser 62 nor total c-MYC was changed in the tumours. However, c-MYC phosphorylation at Thr58/Ser62 (a response target for Akt) was decreased in all tumour types. CYCLIN D1 expression was higher only in NFPAs. The mRNA expression of MEK1, MEK2, ERK1, ERK2, c-MYC and CCND1 was similar in all groups.

Our data indicate that in pituitary adenomas both the Raf/MEK/ERK and PI3K/Akt/mTOR pathways are up-regulated in their initial cascade, implicating a pro-proliferative signal derangement upstream to their point of convergence. However, we speculate that other processes, such as senescence, attenuate the changes downstream in these benign tumours.