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.