Cancer Res 2005,
Wlodarski, Pawel; Kasprzycka, Monika; Liu, Xiaobin; Marzec, Michal; Robertson, Erle S; Slupianek, Artur; Wasik, Mariusz A
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.
Diseases/Pathways annotated by Medline MESH:
Burkitt Lymphoma, Cell Transformation, Viral, MAP Kinase Signaling System
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Text Mining Data
mammalian target of rapamycin — Akt: " Activation of mammalian target of rapamycin
in transformed B lymphocytes is nutrient dependent but independent
, mitogen activated protein kinase/extracellular signal regulated kinase kinase, insulin growth factor-I, and serum "
Akt → PI3K: " Both direct Akt ( Akt inhibitors I-III ) and a PI3K inhibitor ( wortmannin at 1 nmol/L ) suppressed Akt phosphorylation without significantly affecting mTOR activation "
Manually curated Databases
No curated data.