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Concurrent inhibition of PI3-Kinase and mTOR induces cell death in diffuse large B cell lymphomas, a mechanism involving down regulation of Mcl-1

Item Type:Article
Title:Concurrent inhibition of PI3-Kinase and mTOR induces cell death in diffuse large B cell lymphomas, a mechanism involving down regulation of Mcl-1
Creators Name:Zang, C. and Eucker, J. and Liu, H. and Mueller, A. and Possinger, K. and Scholz, C.W.
Abstract:Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling is frequently dysregulated in diffuse large B cell lymphoma (DLBCL) including the favourable germinal centre B-cell (GCB) and the unfavourable activated B-cell (ABC) subtypes. mTOR promotes cap-dependent translation of proteins, like Mcl-1, through inhibitory phosphorylation of the eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). Inhibition of mTOR by RAD001 reduces proliferation but fails to dephosphorylate 4EBP1 and to induce cell death in either DLBCL subtype. In contrast, concurrent inhibition of PI3K and mTOR with NVP-BEZ235 inhibits proliferation, dephosphorylates 4EBP1, and induces cells death, notably more pronounced in CGB cells. Small RNA interference identifies Mcl-1 as a crucial cell death mediator of both DLBCL subtypes. Inhibition of the PI3K/mTOR/4EBP1 by NVP-BEZ235 results in suppression of the cap-dependent translation initiation complex and concomitant downregulation of Mcl-1 in GCB cell lines. In ABC cell lines, this suppression is possibly compensated by NF-{kappa}B- or Pim kinase-mediated signalling.
Keywords:PI3K/Akt/mTOR, NVP-BEZ235, DLBCL, GCB, ABC
Source:Cancer Letters
ISSN:0304-3835
Publisher:Elsevier (Ireland)
Volume:339
Number:2
Page Range:288-297
Date:10 October 2013
Official Publication:https://doi.org/10.1016/j.canlet.2012.11.013
PubMed:View item in PubMed

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