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

D. Dworakowska, E. Wlodek, C. A. Leontiou, S. Igreja, M. Cakir, M. Teng, N. Prodromou, M. Góth, S. Grozinsky-Glasberg, M. Gueorguiev, B. Kola, M. Korbonits, A. B. Grossman

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1329-1338
Number of pages10
JournalEndocrine-Related Cancer
Volume16
Issue number4
DOIs
Publication statusPublished - Dec 2009

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Phosphatidylinositol 3-Kinase
Mitogen-Activated Protein Kinase Kinases
Pituitary Neoplasms
Sirolimus
70-kDa Ribosomal Protein S6 Kinases
Neoplasms
Phosphorylation
Prolactinoma
Messenger RNA
Adrenocorticotropic Hormone
Autopsy
Western Blotting
Polymerase Chain Reaction
Growth
Proteins

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

Cite this

Dworakowska, D., Wlodek, E., Leontiou, C. A., Igreja, S., Cakir, M., Teng, M., ... Grossman, A. B. (2009). Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors. Endocrine-Related Cancer, 16(4), 1329-1338. https://doi.org/10.1677/ERC-09-0101

Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors. / Dworakowska, D.; Wlodek, E.; Leontiou, C. A.; Igreja, S.; Cakir, M.; Teng, M.; Prodromou, N.; Góth, M.; Grozinsky-Glasberg, S.; Gueorguiev, M.; Kola, B.; Korbonits, M.; Grossman, A. B.

In: Endocrine-Related Cancer, Vol. 16, No. 4, 12.2009, p. 1329-1338.

Research output: Contribution to journalArticle

Dworakowska, D, Wlodek, E, Leontiou, CA, Igreja, S, Cakir, M, Teng, M, Prodromou, N, Góth, M, Grozinsky-Glasberg, S, Gueorguiev, M, Kola, B, Korbonits, M & Grossman, AB 2009, 'Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors', Endocrine-Related Cancer, vol. 16, no. 4, pp. 1329-1338. https://doi.org/10.1677/ERC-09-0101
Dworakowska, D. ; Wlodek, E. ; Leontiou, C. A. ; Igreja, S. ; Cakir, M. ; Teng, M. ; Prodromou, N. ; Góth, M. ; Grozinsky-Glasberg, S. ; Gueorguiev, M. ; Kola, B. ; Korbonits, M. ; Grossman, A. B. / Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors. In: Endocrine-Related Cancer. 2009 ; Vol. 16, No. 4. pp. 1329-1338.
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