Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.

By Y. Chien, C. Scuoppo, Xiaowo Wang, X. Fang, B. Balgley, Jessica E. Bolden, P. Premsrirut, Weijun Luo, A. Chicas, C. S. Lee and 2 more. Genes & Development, 2011

978 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/6dc1897ec48a6521984255282828603c81174912

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. J. Campisi
2. Jesús Gil
3. A. Lujambio
4. J. Joyce
5. Scott W. Lowe

In Immunology

1. J. Campisi
2. Jesús Gil
3. V. Krizhanovsky
4. J. Joyce
5. Scott W. Lowe
6. Domhnall McHugh
7. Y. Fouad
8. C. Aanei

In Physiology

1. J. Campisi
2. Jesús Gil
3. Jiandong Chen
4. V. Krizhanovsky
5. Scott W. Lowe
6. Domhnall McHugh
7. Masashi Narita
8. Mahito Sadaie

Citations in the corpus

• Cellular senescence and its effector programs (2014, background): “2008), and two transcription factors, NF-kB and C/EBPb, have been shown to be up-regulated, activated, and bound to chromatin during OIS and to cooperatively regulate the inflammatory components of the SASP (Acosta et al. 2008; Kuilman et al. 2008; Chien et al. 2011; Jing et al. 2011).”
• Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines (2018, background): “Both the redox-sensitive inflammatory pathway and the senescent cellrelated SASP activate the inflammasome through the NF-κB and IL-α cascade, causing persistence of the inflammatory response that delays resolution and healing (125, 138).”
• Aging, Cellular Senescence, and Cancer (2012, background): “The SASP cytokines that are responsible for these immune responses are incompletely understood but are very likely numerous (132, 135).”