Activation of Mammalian Target of Rapamycin in Transformed B Lymphocytes Is Nutrient Dependent but Independent of Akt, Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase, Insulin Growth Factor-I, and Serum.

Research output: Contribution to journalJournal articleResearchpeer-review

  • Pawel Wlodarski
  • Monika Kasprzycka
  • Xiaobin Liu
  • Marzec, Michal Tomasz
  • Erle S. Robertson
  • Artur Slupianek
  • Mariusz A. Wasik
The study examines the preponderance and mechanism of mammalian target of rapamycin (mTOR) activation in three distinct types of transformed B lymphocytes that differ in expression of the EBV genome. All three types [EBV-immortalized cells that express a broad spectrum of the virus-encoded genes (type III latency; EBV+/III), EBV-pos. cells that express only a subset of the EBV-encoded genes (EBV+/I), and EBV-neg., germinal center-derived cells (EBV-)] universally displayed activation of the mTOR signaling pathway. However, only the EBV+/III transformed B cells displayed also activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway that is considered to be the key activator of mTOR and of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway that coactivates one of the immediate targets of mTOR, p70 S6K1. Activation of the PI3K/Akt and MEK/ERK, but not of the mTOR pathway, was inhibited by serum withdrawal and restored by insulin growth factor-I. In contrast, activation of mTOR, but not PI3K/Akt and MEK/ERK, was sensitive to nutrient depletion. Both direct Akt (Akt inhibitors I-III) and a PI3K inhibitor (wortmannin at 1 nmol/L) suppressed Akt phosphorylation without significantly affecting mTOR activation. Furthermore, rapamycin, a potent and specific mTOR inhibitor, suppressed profoundly proliferation of cells from all three types of transformed B cells. U0126, a MEK inhibitor, had a moderate antiproliferative effect only on the EBV+/III cells. These results indicate that mTOR kinase activation is mediated in the transformed B cells by the mechanism(s) independent of the PI3K/Akt signaling pathway. They also suggest that inhibition of mTOR signaling might be effective in therapy of the large spectrum of B-cell lymphomas. [on SciFinder(R)]
Original languageEnglish
JournalCancer Research
Issue number17
Pages (from-to)7800-7808
Number of pages9
Publication statusPublished - 2005
Externally publishedYes

Bibliographical note

M1 - Copyright (C) 2018 American Chemical Society (ACS). All Rights Reserved.

CAPLUS AN 2005:972191(Journal)

    Research areas

  • B lymphocyte nutrient signaling transformation IGF lymphoma

ID: 202376216