Lack of compensatory pAKT activation and eIF4E phosphorylation of lymphoma cells towards mTOR inhibitor, RAD001
Journal
European Journal of Cancer
Journal Volume
47
Journal Issue
8
Pages
1244-1257
Date Issued
2011
Author(s)
Chen L.-T.
Lin C.-H.
Yeh P.-Y.
Jeng H.-J.
Gao M.
Abstract
mTOR (mammalian target of rapamycin) inhibitors were recently found to be effective in the treatment of various human non-Hodgkin's lymphomas (NHLs). We recently reported that RAD001, an mTOR inhibitor, suppressed the growth of lymphoma cells at concentrations much lower than those required for carcinomas. However, the basis for the enhanced sensitivity to RAD001 is unknown. Seven aggressive NHL cell lines and seven carcinoma cell lines were used in this study. Cell cycle was analysed by flow cytometry. pAKT (phosphorylated AKT) (Ser 473 and Thr 308), p-p70S6K, p-4E-BP1, p-mTOR, p-eIF4E (phosphorylated eIF4E), cyclin A, cyclin E, cyclin D3, c-Myc and insulin receptor substrate-1 (IRS-1) protein expression were assessed by immunoblotting. The PI3K/AKT/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) signalling pathway was constitutively expressed in all seven lymphoma cell lines. RAD001 down-regulated p-mTOR, p-p70S6K, p-4E-BP1, cyclin A, cyclin E, cyclin D3, and c-Myc, but did not affect IRS-1. In parallel with RAD001-induced inhibition of cell viability, a dose- and schedule- dependent down-regulation of pAKT and p-eIF4E expressions was demonstrated. In contrast, a compensatory activation of pAKT and p-eIF4E, was observed in seven carcinoma cells. These findings indicate that the basis for enhanced activity of mTOR inhibitors in NHL may be the lack of compensatory activation of AKT and eIF4E phosphorylation in lymphoma cells. ? 2010 Elsevier Ltd. All rights reserved.
SDGs
Other Subjects
cyclin A; cyclin D3; cyclin E; everolimus; initiation factor 4E; insulin receptor substrate 1; mammalian target of rapamycin; Myc protein; phosphatidylinositol 3 kinase; protein kinase B; protein p27; article; cancer growth; cell cycle arrest; cell strain HepG2; cell viability; controlled study; down regulation; enzyme activation; flow cytometry; human; human cell; immunoblotting; immunohistochemistry; leukemia cell line; liver cell carcinoma; lymphoma; nasopharynx carcinoma; priority journal; protein expression; protein phosphorylation; signal transduction; stomach carcinoma; Apoptosis; Carcinoma; Cell Cycle; Cell Line, Tumor; Eukaryotic Initiation Factor-4E; Gene Expression Regulation, Neoplastic; Humans; Immunosuppressive Agents; Jurkat Cells; Lymphoma; Models, Biological; Phosphorylation; Proto-Oncogene Proteins c-akt; Sirolimus; Tetrazolium Salts; Thiazoles; TOR Serine-Threonine Kinases
Type
journal article