Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
- 6 October 2011
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 25 (20), 2125-2136
- https://doi.org/10.1101/gad.17276711
Abstract
Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-κB (NF-κB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-κB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-κB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-κB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-κB that contributes to the outcome of cancer therapy.Keywords
This publication has 59 references indexed in Scilit:
- A Rapid and Scalable System for Studying Gene Function in Mice Using Conditional RNA InterferenceCell, 2011
- Inflammatory networks during cellular senescence: causes and consequencesTrends in Molecular Medicine, 2010
- Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular SenescenceCancer Cell, 2010
- Chronic active B-cell-receptor signalling in diffuse large B-cell lymphomaNature, 2010
- Requirement for NF-κB signalling in a mouse model of lung adenocarcinomaNature, 2009
- RelA/p65 functions to maintain cellular senescence by regulating genomic stability and DNA repairEMBO Reports, 2009
- Chronic NF-κB activation delays RasV12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint responseMechanisms of Ageing and Development, 2009
- Senescence of Activated Stellate Cells Limits Liver FibrosisCell, 2008
- Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7Cell, 2008
- NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasiaNature, 2003