Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL
| Autor: | Pavel Klener, Klaus Schulze-Osthoff, Karsten Boldt, Philipp Berning, Martina Konantz, Michael Grau, Georg Lenz, Caroline Schönfeld, Wendan Xu, Philip Bucher, Petra Vockova, Mohamed Ali Jarboui, Anja Schmitt, Andreas Rosenwald, German Ott, Melanie Grimm, Claudia Lengerke, Marc Brändle, Heike Horn, Stephan Hailfinger, Myroslav Zapukhlyak |
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| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
Dimethyl fumarate biology Chemistry Immunology Germinal center Cell Biology Hematology GPX4 Biochemistry chemistry.chemical_compound medicine.anatomical_structure immune system diseases hemic and lymphatic diseases medicine biology.protein Cancer research Signal transduction Janus kinase STAT3 B cell |
| Zdroj: | Blood. 138:871-884 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2–specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs. |
| Databáze: | OpenAIRE |
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