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.
abstract: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is frequently dysregulated in diffuse large B cell lymphoma (DLBCL) including the favorable germinal centre B-cell (GCB) and the unfavorable 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-κB- or Pim kinase-mediated signaling.
authors.affiliation: Charité-Universitätsmedizin Berlin, Department of Oncology and Hematology, Berlin, Germany.
authors.forename: Chuanbing
authors.initials: C
authors.lastname: Zang
authors.forename: Jan
authors.initials: J
authors.lastname: Eucker
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liu
authors.forename: Anja
authors.initials: A
authors.lastname: Müller
authors.forename: Kurt
authors.initials: K
authors.lastname: Possinger
authors.forename: Christian Wilfried
authors.initials: CW
authors.lastname: Scholz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D000068338:Everolimus; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007093:Imidazoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D000068338:Everolimus; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C406031:proto-oncogene proteins pim; C531198:dactolisib; D020123:Sirolimus