A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein {beta} and NF-{kappa}B activity in Hodgkin and anaplastic large cell lymphomas.
The immunosuppressive macrolide rapamycin and its derivative everolimus (SDZ RAD, RAD) inhibit the mammalian target of rapamycin (mTOR) signaling pathway. In this study, we provide evidence that RAD has profound antiproliferative activity in vitro and in NOD/SCID mice in vivo against Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) cells. Moreover, we identified 2 molecular mechanisms that showed how RAD exerts antiproliferative effects in HL and ALCL cells. RAD down-regulated the truncated isoform of the transcription factor CCAAT enhancer binding protein beta (C/EBPbeta), which is known to disrupt terminal differentiation and induce a transformed phenotype. Furthermore, RAD inhibited constitutive nuclear factor kappaB (NF-kappaB) activity, which is a critical survival factor of HL cells. Pharmacologic inhibition of the mTOR pathway by RAD therefore interferes with essential proliferation and survival pathways in HL and ALCL cells and might serve as a novel treatment option.
Jundt
Franziska
F
Charité, Campus Virchow-Klinikum, University Medicine Berlin, Augustenburger Platz 1, D-13 353 Berlin, Germany. fjundt@mdc-berlin.de
Raetzel
Nina
N
Müller
Christine
C
Calkhoven
Cornelis F
CF
Kley
Katharina
K
Mathas
Stephan
S
Lietz
Andreas
A
Leutz
Achim
A
Dörken
Bernd
B
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D000068338:Everolimus; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D014183:Transplantation, Heterologous
D022782:CCAAT-Enhancer-Binding Protein-beta; D016328:NF-kappa B; D000068338:Everolimus; D020123:Sirolimus