Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity Journal Article
| Authors: | Chien, Y.; Scuoppo, C.; Wang, X.; Fang, X.; Balgley, B.; Bolden, J. E.; Premsrirut, P.; Luo, W.; Chicas, A.; Lee, C. S.; Kogan, S. C.; Lowe, S. W. |
| Article Title: | Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity |
| 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. © 2011 by Cold Spring Harbor Laboratory Press. |
| Keywords: | controlled study; human cell; nonhuman; mouse; phenotype; animals; mice; cell survival; gene expression; cell line; animal experiment; animal model; rna, small interfering; cyclophosphamide; immunoglobulin enhancer binding protein; transcription factor rela; drug resistance; chemosensitivity; cell line, tumor; protein p53; gene expression regulation, neoplastic; chromatin; lymphoma; fibroblast; protein secretion; tumor suppressor protein p53; natural killer cell; senescence; doxycycline; tetracycline; cell aging; short hairpin rna; synaptotagmin i; chemoresistance; protein synthesis inhibitors; sasp; senescence associated secretory phenotype; nf-?b |
| Journal Title: | Genes and Development |
| Volume: | 25 |
| Issue: | 20 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2011-10-15 |
| Start Page: | 2125 |
| End Page: | 2136 |
| Language: | English |
| DOI: | 10.1101/gad.17276711 |
| PROVIDER: | scopus |
| PMCID: | PMC3205583 |
| PUBMED: | 21979375 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 9 December 2011" - "CODEN: GEDEE" - "Source: Scopus" |
