title: Lack of compensatory pAKT activation and eIF4E phosphorylation of lymphoma cells towards mTOR inhibitor, RAD001.
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.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taiwan. shkuo101@ntu.edu.tw
authors.forename: Sung-Hsin
authors.initials: SH
authors.lastname: Kuo
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Hsu
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.forename: Yen-Sen
authors.initials: YS
authors.lastname: Lu
authors.forename: Ching-Huang
authors.initials: CH
authors.lastname: Lin
authors.forename: Pei-Yen
authors.initials: PY
authors.lastname: Yeh
authors.forename: Huei-Jiuan
authors.initials: HJ
authors.lastname: Jeng
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.forename: Kun-Huei
authors.initials: KH
authors.lastname: Yeh
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D000068338:Everolimus; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019169:Jurkat Cells; D008223:Lymphoma / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D007166:Immunosuppressive Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D000068338:Everolimus; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C022616:thiazolyl blue; D020123:Sirolimus