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. 2005 Sep 1;65(17):7800-8.
doi: 10.1158/0008-5472.CAN-04-4180.

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

Pawel Wlodarski  1 , Monika Kasprzycka, Xiaobin Liu, Michal Marzec, Erle S Robertson, Artur Slupianek, Mariusz A Wasik
Affiliations

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

Pawel Wlodarski et al. Cancer Res. .

Abstract

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-positive cells that express only a subset of the EBV-encoded genes (EBV+/I), and EBV-negative, 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.

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