Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
Open accessAbstract
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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NF-κB and C/EBP-β are positive regulators of SASP factor expression.
“First, the transcription factors nuclear factor κB (NF‐κB) and CCAAT/enhancer‐binding protein (C/EBP‐β) were identified as positive regulators of SASP factor expression.”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [49]
The section “NF-kB controls the SASP” reports that inhibiting NF-κB prevents induction of several SASP components, supporting its role as a positive regulator. “Identification and activation of NF-kB in senescent cells” identifies C/EBP-β as a known senescence regulator enriched on senescent chromatin, but does not show that it positively regulates SASP factor expression. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGiven the proinflammatory nature of the SASP, senescent cells can attract immune cells, including destructive leukocytes of the innate and adaptive immune systems.
“Given the proinflammatory nature of the SASP, it is not surprising that senescent cells can attract immune cells, including destructive leukocytes of the innate and adaptive immune systems (131, 132, 135).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [135]
The introductory passage (page unavailable) says SASP factors attract immune cells that can eliminate senescent cells. The NF-κB controls the SASP section reports targeting by natural killer cells, and the drug-induced senescence section reports immune-cell infiltration, especially NK cells. Our copy does not establish attraction of destructive leukocytes from both the innate and adaptive immune systems. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe SASP cytokines responsible for these immune responses are incompletely understood but are very likely numerous.
“The SASP cytokines that are responsible for these immune responses are incompletely understood but are very likely numerous (132, 135).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [135]
The Abstract says IL-6, IL-8, and other secreted factors attract immune cells, and the ‘NF-kB controls the SASP’ section identifies multiple immune-response genes. This supports the involvement of several SASP factors, but the paper does not establish that numerous cytokines are responsible for the immune responses or explicitly say that their identities are incompletely understood. Its statement that little is known concerns regulation of the SASP, not which cytokines mediate immunity. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAmong the cells that participate in clearance of senescent cells are natural killer cells, macrophages, and T cells.
“Among the cells that participate in the clearance of senescent cells are natural killer cells, macrophages, and T cells (131, 135, 139).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [135]
The NF-κB controls the SASP section reports that natural killer cells target senescent cells, and the figure caption describes their recognition and killing of those cells. The paper does not identify macrophages or T cells as clearing senescent cells; its mention of macrophages concerns apoptotic cells in lymph nodes. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNF-κB, p38, mTOR and C/EBPβ signalling pathways are major components of the SASP.
“The NF- κB, p38, mTOR and C/EBPβ signalling pathways are major components of the SASP 63-67 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [64]
The ‘NF-kB controls the SASP’ section shows that suppressing NF-κB prevents induction of several SASP factors, and the Discussion calls NF-κB a major transcriptional modulator required for the SASP. The passages do not establish p38, mTOR or C/EBPβ signalling as major SASP components, so this paper supports only the NF-κB part of the sentence. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
At least some SASP components can be chemosensitizing.
“In contrast, at least some SASP components can be chemosensitizing.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [135]
Global suppression of the SASP through NF-κB inhibition promoted resistance to chemotherapy in a mouse lymphoma model.
“For example, global suppression of the SASP (through NF-κB inhibition) promoted resistance to chemotherapy in a mouse lymphoma model (135).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [135]
In senescent fibroblasts and oncogene-induced senescence, the SASP is closely controlled by NF-κB signalling.
“In senescent fibroblasts and in oncogene-induced senescence, the SASP is closely controlled by signalling through NF-κB1617.”
From Chronic inflammation induces telomere dysfunction and accelerates ageing in mice (2014) · cites this paper as [16]
DRISR closest to ATAC-UP regions were significantly enriched (q-value < 0.05) in 43 motifs, including NF-κB, Jun-AP1, Batch2, Stat3, HIF-1α, and CTCF.
“The results indicated that the DRISR closest to ATAC-UP regions were significantly enriched (q-value < 0.05) in 43 motifs (Fig. 2F), including NF-κB (35), Jun-AP1 (36), Batch2 (37), Stat3, HIF-1α, and CTCF (11, 21), which are known to be involved in cellular senescence or inflammatory SASP gene expression.”
From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [35]
Most cascades involved in inducing and dynamically regulating SASP ultimately converge on activation of two transcription factors, NF-κB and CEBPβ, which are enriched in chromatin fractions of senescent cells.
“Most of the cascades involved in inducing and dynamically regulating SASP ultimately converge on the activation of two transcription factors, NF-κB and CEBPβ which are found to be enriched in the chromatin fractions of senescent cells (Acosta et al., 2008; Kuilman et al., 2008; Chien et al., 2011; Ohanna et al., 2011; Huggins et al., 2013).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Chien et al., 2011
NF-κB has a crucial role in controlling the SASP.
“NF-κB has a crucial role in controlling the SASP (18, 19, 49) (Fig. 3D)”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [49]
Inhibition of NF-κB abrogated p53-mediated senescence.
“Even more upstream, inhibition of nuclear factor κB (NF-κB) abrogated p53-mediated senescence.55”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [55]
Most SASP regulators converge to C/EBP-β and NF-κB transcription factors that cooperatively regulate SASP factor induction in various senescence contexts.
“Most SASP regulators converge to the CCAAT/enhancer-binding protein β (C/EBP-β) and nuclear factor kappa-B (NF-κB) transcription factors that cooperatively regulate SASP factors induction in various senescence contexts [153,154,155].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [155]
NF-κB inhibition in senescent cells selectively represses SASP genes that require this transcription factor.
“Considering the central role of NF-κB transcriptional activity in SASP induction, NF-κB inhibition in senescent cells selectively represses SASP genes that require this transcription factor [155].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [155]
As p53 response efficiency declines during aging, aerobic glycolysis is increased as well as the proinflammatory SASP via NF-κB signaling.
“As the p53 response efficiency declines during aging [228], aerobic glycolysis is increased as well as the proinflammatory SASP via NF-κB signaling [155].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [155]
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Oncogene-induced senescence: From biology to therapy
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- 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.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Tsinghua University (CN)
- University of Maryland, College Park (US)
- University of California, San Francisco (US)
- Memorial Sloan Kettering Cancer Center (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-10-06
- Volume
- 25
- Issue
- 20
- Pages
- 2125-2136
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3205583
- OpenAlex
- W2061765285
- Semantic Scholar
- 6dc1897ec48a6521984255282828603c81174912
- Cited by
- 1,046
- References
- 59
- Citations by year
- 2026: 104 · 2025: 101 · 2024: 100 · 2023: 68 · 2022: 95 · 2021: 96 · 2020: 81 · 2019: 73 · 2018: 73 · 2017: 40 · 2016: 68 · 2015: 43 · 2014: 34 · 2013: 40 · 2012: 26
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Leukemia and Lymphoma Society
- National Institutes of Health
- National Institute on Aging (R56AG016379, AG-16379, R01AG016379)
- National Cancer Institute (CA 122715, R42CA122715, R21CA143177, CA 143177, R41CA122715)
- National Institute of General Medical Sciences (T32GM008444)
- National Center for Research Resources (RR 021239, R44RR021239, R43RR021239)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, senescence-associated secretory phenotype, NF-κB, NF-κB p65, chemosensitivity, drug resistance, p53, Rb, natural killer cells, tumor suppression, lymphoma, senescence escape
- MeSH terms
- Animals, Cell Line, Cell Survival, Drug Resistance, Humans, Lymphoma, Phenotype, Protein Synthesis Inhibitors, Tetracycline, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cellular Senescence, RNA, Small Interfering, Cell Line, Tumor, Mice, Transcription Factor RelA
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