Nuclear Factor-kappa B (NFκB) is an important transcription factor involved in many biological phenomena such as cancer, inflammation, aging, and immune response. The canonical pathway of NFκB has multiple feedbacks, and the NFκB activation display oscillation behavior. NFκB inhibitor alpha (IκBα) is a target gene of NFκB, but is also a negative feedback factor and cause oscillation of NFκB activity. Knockout of the IκBα gene induces sustained NFκB activation in cells stimulated with tumor necrosis factor α (TNFα), resulting in gene expression different from oscillatory NFκB activation (Cheng et al., Science, 2021). However, how this change in the dynamics of NFκB activity link to cell properties or fate is not fully understood.
In breast cancer MCF7 cells, the IκBα knockdown-induced sustained NFκB activation promoted cellular senescence phenotypes such as increased cell size, cell cycle arrest, elevated SA-βgal activity, and senescence-associated secretory phenotype (SASP) gene expression. Furthermore, combined metabolomic and transcriptomic analysis revealed that sustained activation of NFκB leads to metabolic hallmarks associated with cellular senescence. In this presentation, we would like to discuss the molecular mechanisms by which dynamics change in NFκB activity induce cellular senescence from the viewpoint of metabolism.