Phosphorylated 4E-binding protein 1 (p-4E-BP1): A novel prognostic marker in human astrocytomas

Penelope Korkolopoulou, Georgia Levidou, Elias A. El-Habr, Christina Piperi, Christos Adamopoulos, Vassilis Samaras, Efstathios Boviatsis, Irene Thymara, Eleni Andriana Trigka, Stratigoula Sakellariou, Nikolaos Kavantzas, Efstratios Patsouris, Angelica A. Saetta

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Aims: To investigate the significance of the mammalian target of rapamycin (mTOR) pathway in astrocytic tumours, published information in this context being limited, especially regarding phosphorylated 4E-binding protein (p-4E-BP) 1. Methods and results: Paraffin-embedded tissue from 111 patients with astroglial tumours (grades II-IV) was investigated for the association of phosphorylated mTOR (p-mTOR) signalling components with phosphorylated extracellular signal-related kinase 1/2 (p-ERK1/2) and phosphorylated AKT (p-AKT) expression, clinicopathological features, angiogenesis, isocitrate dehydrogenase 1 (IDH1)-R132H, and survival. Expression was also quantified by western blot analysis in 12 cases and in three primary glioma cell cultures following rapamycin treatment. p-mTOR expression correlated with p-4E-BP1 expression and marginally with p-p70S6K expression. p-4E-BP1 expression increased with tumour grade. Rapamycin induced a decline in phosphorylation levels of all three proteins. Nuclear p-AKT and cytoplasmic p-ERK1/2 immunoexpression correlated with p-4E-BP1 expression, whereas cytoplasmic p-AKT expression correlated with p-p70S6K expression. All three proteins were associated with increased angiogenesis but not with IDH1-R132H expression status. p-mTOR adversely affected overall and disease-free survival in univariate analysis. In multivariate survival analysis, the presence of p-4E-BP1 predicted shortened overall survival in the entire cohort and glioblastomas. Conclusions: mTOR signalling components are differentially involved in the acquisition of a more aggressive and angiogenic phenotype in astrocytic tumours. Moreover, p-4E-BP1 emerges as a novel prognostic marker, which might aid in the selection of patients who are more likely to benefit from therapy with mTOR inhibitors.

Original languageEnglish
Pages (from-to)293-305
Number of pages13
JournalHistopathology
Volume61
Issue number2
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • Angiogenesis
  • Astrocytomas
  • IDH1-R132H
  • P-4E-BP1
  • P-mTOR
  • P-p70S6K

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