Glutaminase inhibition as a potential therapeutic strategy in diffuse large B-cell lymphoma

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dc.contributor.advisor Hailfinger, Stephan (Prof. Dr.) Gomez Solsona, Beatriz 2023-08-10T12:13:56Z 2023-08-10T12:13:56Z 2025-07-04
dc.identifier.uri de_DE
dc.description.abstract Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease and the most prevalent lymphoma in adulthood. Despite the existence of a first-line chemoimmunotherapy regime, approximately one-third of patients remain unresponsive and succumb to the disease, highlighting the need to find novel treatment strategies. In this regard, tumor cells frequently exhibit metabolic reprogramming and become addicted to glutamine, relying on this amino acid and its metabolism to fulfill their bioenergetic and biosynthetic demands, and to maintain homeostasis. This dependency on glutamine becomes a vulnerability that can be exploited therapeutically. Taking this into account, the aim of this study was to investigate the dependence of DLBCL cells on glutaminolysis, as well as exploring the effects and potential of targeting the enzyme glutaminase-1 (GLS1) for the treatment of DLBCL. In the present study, we could show that GLS1 is robustly expressed in multiple DLBCL cell lines. Accordingly, we demonstrated that both pharmacological inhibition and genetic knockdown of GLS1 induce cell death in DLBCL cells independent of their subtype classification and genetic characteristics. Conversely, primary human B-cells remained refractory to this treatment. Interestingly, GLS1 inhibition provoked a stark decrease in common tricarboxylic acid cycle (TCA) intermediaries and, most importantly, significantly increased the levels of cytosolic and mitochondrial reactive oxygen species (ROS). We noticed that the accumulation of ROS upon glutaminase inhibition in DLBCL cells can be partially attributed to the decrease in reduced glutathione (GSH) levels. In this context, we demonstrated that supplementation with a membrane-permeable form of ɑ-ketoglutarate or with thepotent antioxidant ɑ-tocopherol recovered the pool of reduced GSH, attenuated oxidative stress and abrogated the cytotoxicity caused by GLS1 inhibition. Moreover, we examined the effects of combining the GLS1 inhibitor CB-839 with the Bcl-2 inhibitor ABT-199 and observed that this combination not only increases ROS production dramatically, but also induces DLBCL cytotoxicity in a synergistic manner. Collectively, our data defines the crucial role of glutaminolysis for the survival of DLBCL cells through the maintenance of redox homeostasis and highlight the potential of targeting GLS1 and Bcl-2 simultaneously for the treatment of DLBCL patients. en
dc.description.abstract Dissertation ist gesperrt bis 04.07.2025 ! de_DE
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri de_DE
dc.rights.uri en
dc.subject.classification Lymphom , B-Zell-Lymphom , Non-Hodgkin-Lymphom , Apoptosis , Glutaminase , Inhibition , Reaktive Sauerstoffspezies de_DE
dc.subject.ddc 500 de_DE
dc.subject.ddc 540 de_DE
dc.subject.ddc 570 de_DE
dc.subject.ddc 610 de_DE
dc.subject.other Diffuse large B-cell lymphoma, B-cell lymphoma, glutaminase inhibition, synergism, apoptosis en
dc.title Glutaminase inhibition as a potential therapeutic strategy in diffuse large B-cell lymphoma en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2023-07-04
utue.publikation.fachbereich Biochemie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.noppn yes de_DE


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