Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
| Autor: | Scott C. Kogan, Xiaowo Wang, Weijun Luo, Cheng S. Lee, Jessica E. Bolden, Xueping Fang, Claudio Scuoppo, Prem K. Premsrirut, Scott W. Lowe, Agustin Chicas, Yuchen Chien, Brian M. Balgley |
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| Rok vydání: | 2011 |
| Předmět: |
Senescence
Cell cycle checkpoint Lymphoma Cell Survival Drug Resistance Biology medicine.disease_cause Cell Line Mice chemistry.chemical_compound Cell Line Tumor Genetics medicine Animals Humans RNA Small Interfering Transcription factor Cellular Senescence Protein Synthesis Inhibitors Transcription Factor RelA NF-κB Tetracycline Chromatin Gene Expression Regulation Neoplastic Phenotype chemistry Cell culture Cancer research Tumor Suppressor Protein p53 Carcinogenesis Cell aging Developmental Biology |
| Zdroj: | Genes & Development. 25:2125-2136 |
| ISSN: | 1549-5477 0890-9369 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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