Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults and reveals distinct genetic and metabolic signatures. NF-κB transcription factor family is involved in diverse biological processes enabling tumor development and resistance to anticancer-therapy through activation of its two main pathways, the canonical and the alternative NF-κB pathways, the main actor of the latter being the RelB NF-kB subunit. RelB DNA binding activity is frequently activated in DLBCL patients and cell lines. RelB activation defines a new DLBCL subgroup with dismal outcome upon immunochemotherapy, and RelB confers DLBCL cell resistance to DNA damage. However, whether RelB can impact on DLBCL cell metabolism and survival upon metabolic stress is unknown. Here, we reveal that RelB controls DLBCL oxidative energetic metabolism. Accordingly, RelB inhibition reduce DLBCL mitochondrial ATP production, and sensitizes DLBCL cells to apoptosis induced by Metformin and L-asparaginase (®Kidrolase), two FDA approved antimetabolic drugs targeting mitochondrial metabolism. RelB also confers DLBCL cell resistance to glutamine deprivation, an essential amino acid that feeds the TCA cycle. Taken together, our findings uncover a new role for RelB in the regulation of DLBCL cell metabolism and DLBCL cell survival upon metabolic stress.
Highlights
IntroductionNF-κB is a family of transcription factors that are key players in cell survival, immune and inflammatory responses [1,2,3]
To directly assess the contribution of RelB on Diffuse large B-cell lymphoma (DLBCL) cell survival upon mitochondrial stress, we used the activated B-cell-like (ABC) DLBCL cell line MD901 that we have previously described as exhibiting a strong constitutive RelB DNA-binding activity [25]
Since the metabolic status of the MD901 DLBCL cell line was so far unknown, we evaluated whether this DLBCL
Summary
NF-κB is a family of transcription factors that are key players in cell survival, immune and inflammatory responses [1,2,3]. In mammals, it is composed of five structurally related members forming homo- or heterodimers: RelA ( known as p65), RelB, cRel (Rel), NF-κB1 (p50 and its precursor p105) and NF-κB2 (p52 and its precursor p100) [4]. Its activity is regulated through two main signaling cascades: the classical or canonical NF-κB pathway, in which mainly participate RelA and/or c-Rel containing complexes; and the alternative or non-canonical NF-κB pathway that leads to the activation of RelB containing dimers [5,6,7]
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