Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors.

Journal article

Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascades are key signalling pathways interacting with each other to regulate cell growth and tumourigenesis. We have previously shown B-Raf and Akt overexpression and/or overactivation in pituitary adenomas. The aim of this study is 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), six GH-omas, six prolactinomas and six 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 subtypes 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 upregulated 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.

Authors: Dworakowska, D; Wlodek, E; Leontiou, C; Igreja, S; Cakir, M

• Publication status: Published
• Journal: Endocrine-related cancer
• Volume: 16
• Issue: 4
• Pages: 1329-1338
• Publication date: 2009-12-01
• DOI: 10.1677/erc-09-0101
• EISSN: 1479-6821
• ISSN: 1351-0088
• Language: English
• Keywords: Female; Immunoenzyme Techniques; Adult; Reverse Transcriptase Polymerase Chain Reaction; Phosphatidylinositol 3-Kinases; Intracellular Signaling Peptides and Proteins; Cell Proliferation; Humans; Phosphorylation; Cyclin D1; Aged; MAP Kinase Kinase Kinases; TOR Serine-Threonine Kinases; Pituitary Neoplasms; Proto-Oncogene Proteins c-akt; Young Adult; Case-Control Studies; RNA, Messenger; Mitogen-Activated Protein Kinase 3; Middle Aged; Proto-Oncogene Proteins c-myc; Signal Transduction; Male; Protein-Serine-Threonine Kinases; raf Kinases; Blotting, Western