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.
authors: Cold Spring Harbor Laboratory, New York 11724, USA.
authors: Yuchen
authors: Y
authors: Chien
authors: Claudio
authors: C
authors: Scuoppo
authors: Xiaowo
authors: X
authors: Wang
authors: Xueping
authors: X
authors: Fang
authors: Brian
authors: B
authors: Balgley
authors: Jessica E
authors: JE
authors: Bolden
authors: Prem
authors: P
authors: Premsrirut
authors: Weijun
authors: W
authors: Luo
authors: Agustin
authors: A
authors: Chicas
authors: Cheng S
authors: CS
authors: Lee
authors: Scott C
authors: SC
authors: Kogan
authors: Scott W
authors: SW
authors: Lowe
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004351:Drug Resistance / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D013752:Tetracycline