Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity (original) (raw)

  1. Claudio Scuoppo2,9,
  2. Xiaowo Wang3,
  3. Xueping Fang4,
  4. Brian Balgley5,
  5. Jessica E. Bolden1,
  6. Prem Premsrirut1,
  7. Weijun Luo1,
  8. Agustin Chicas1,
  9. Cheng S. Lee4,
  10. Scott C. Kogan6 and
  11. Scott W. Lowe1,7,8,10
  12. 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
  13. 2Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
  14. 3Ministry of Education (MOE) Key Laboratory of Bioinformatics, Bioinformatics Division, Tsinghua National Laboratory for Information Science and Technology (TNLIST), Department of Automation, Tsinghua University, Beijing 10084, China;
  15. 4Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, USA;
  16. 5Calibrant, Gaithersburg, Maryland 20878, USA;
  17. 6Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA;
  18. 7Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA;
  19. 8Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
  20. ↵9 These authors contributed equally to this work.

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.

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