Control of senescence by CXCR2 and its ligands
Open accessAbstract
Senescence is an irreversible growth arrest with important physiological implications as it contributes to tumour suppression and may have a role in aging. During senescence, cells suffer profound phenotypic changes affecting amongst others cell morphology and chromatin structure. Senescent cells also undergo significant transcriptional changes, such as the increased production of a plethora of different secreted factors, which are the basis of the so-called senescence-associated secretory phenotype. While some of these factors have been previously shown to possess different pro-tumorigenic activities, we recently demonstrated that the secretion of CXCR2-binding chemokines (such as IL-8 or GROalpha) by senescent cells contribute to reinforce senescence via activation of the p53 pathway. Importantly, our data adds to that presented by several groups suggesting that also other factors secreted during senescence (such as PAI-1, IGFBP-7 or IL-6) contribute to the senescent response. Here, we discuss our findings in the context of the emerging role for secreted factors in regulating senescence through paracrine and/or autocrine mechanisms.
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The SASP can recruit immune cells that mediate tumor clearance or promote paracrine senescence.
“On one hand, the SASP can induce the recruitment of immune cells that will mediate tumor clearance (Xue et al., 2007), or promote paracrine senescence (Acosta et al., 2013; Acosta et al., 2008).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Acosta et al., 2008
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“…group, we also noted a high representation of the Wnt signaling pathway and cytokine–cytokine receptor interactions, two pathways previously linked with cellular senescence (Ye et al., 2007; Acosta et al. 2008; Coppe et al., 2010b); however, in both cases, statistical significance was rather weak.”
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“Along with IL-6, CXCLl is one of the cytokines associated with senescence-associated secretory program (SASP) [35, 36].”
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“Whereas some of these factors can induce proliferative responses in a paracrine manner,(15) it is now clear that at least some others, namely IL-6, IL-8 and IGFBP7, have a causal role in the induction and maintenance of both replicative and OIS, in an autocrine manner.(16,17,19) It is now well established that senesce…”
BackgroundHMGB2 holds the key to the senescence-associated secretory phenotype
Guerrero, A., & Gil, J. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201610044 · Cited by 30 · see citing works
“Remarkably, Aird et al. (2016) observed that the decrease in chromatin-bound HMGB2 correlated with reduced SASP gene expression but did not affect cell cycle arrest.”
BackgroundMethodInfluentialSelf-citationHeß, J., Unger, K., Orth, M., Schötz, U., Schüttrumpf, L., Zangen, V., Gimenez-Aznar, I., Michna, A., Schneider, L., Stamp, R., et al. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.11.014 · Cited by 30 · see citing works
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“It has been reported that senescent cells activate a self-amplifying secretory program in which CXCR2 ligands reinforce growth arrest [78,79].”
BackgroundConstitutively Active Chemokine CXC Receptors
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“Acosta and colleagues [11,17,18] found that depletion of the CXCR2 receptor delayed both replicative senescence and impaired the response to oncogenic signals suggesting that signaling by CXCL1 might limit tumor growth by reinforcing senescence during tumorigenesis.”
BackgroundModulation of immune responses by the tumor suppressor p53
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“In addition, ROS production and subsequent premature senescence in response to CXCR2 activation is partially dependent on p53 [78].”
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“IL8 is an important component of SASP (6), which may contribute to reinforce autocrine senescent cell-growth arrest (7) and has been found to be highly increased in media conditioned by senescent endothelial cell cultures (8).”
Protect and serve: Bcl-2 proteins as guardians and rulers of cancer cell survival
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“Several approaches have shown that NFκB is involved in the secretion of pro-inflammatory mediators and by cells undergoing senescence.(77,78) This senescence-associated secretory phenotype (SASP) can be deleterious or beneficial to the cell, as it can either enforce senescence and recruit immune cells to clear senesce…”
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“MCP-1 relays and reinforces senescence signaling by increasing the protein levels of p53 and p21 via ROS or p38 MAPK signaling [33,34].”
BackgroundAutofluorescence-based sorting removes senescent cells from mesenchymal stromal cell cultures
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Rapamycin induces pluripotent genes associated with avoidance of replicative senescence
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“Senescent morphology is characterized by cell hypertrophy, cell flattening, hyper-secretory phenotype, and SA-βGal staining.(1-3,5,9-19) This senescent morphology depends in part on the mTOR signaling pathway.”
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“3,38–40 However, the introduction of CXCR2 and its ligands by K‐RAS reinforces senescence in vitro.(41) CXCR2 inhibition but not”
BackgroundThe Importance of Senescence in Ionizing Radiation-Induced Tumour Suppression
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“Rac in turn increases production of reactive oxygen species by NADPH oxidases, which provoke or sensitize to DNA damage (Acosta et al., 2008).”
BackgroundInfluentialCombination Therapies to Improve the Efficacy of Immunotherapy in Triple-negative Breast Cancer
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“Inflammatory factors, such as IL-6 and IL-8, contribute to cellular growth arrest and senescence [30, 31].”
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“Similar to the current findings, previous studies have shown that IL-8 and GROa lead to enhanced senescence in fibroblasts through autocrine and paracrine action via CXCR2, regulating the DDR via Rb/p16 and p53/21 signaling [40,41].”
ResultAberrant signaling and senescence associated protein degradation
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“Senescent cells secrete a variety of pro-in fl ammatory modulators that can reinforce thesenescencestateinacellautonomousmannerandpropagatethese-nescent phenotype to neighbouring cells (Acosta et al., 2013; Acosta et al., 2008a; Acosta et al., 2008b).”
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“Others, such as IL6 and IL8, can have either effect depending on context[31,35,36,37].”
BackgroundCell Senescence in Myxoid/Round Cell Liposarcoma
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“More recently IL6 and IL8 were reported to be parts of a cytokine expression profile (IL6 and IL8) that is typical for senescent cells [34–36].”
BackgroundCellular Senescence is a Common Characteristic Shared by Preneoplasic and Osteo-Arthritic Tissue
Brondello, J., Philipot, D., Djouad, F., Jørgensen, C., & Noël, D. (2010) · The Open Rheumatology Journal · doi:10.2174/1874312901004010010 · Cited by 13 · see citing works
“Furthermore, IL-8/CXCR2 tandem is transcriptionally induced by the DDR and participates to the senescence-dependent cell cycle arrest by producing more ROS [39].”
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“…growth factors (Yang et al., 2006)], proteases (Finkel et al., 2007), insoluble proteins, and extracellular matrix components (Acosta et al., 2008a; Acosta et al., 2008b), which mediated cell proliferation, invasion, and migration (Wald et al., 2011; Han et al., 2015; Ku ź nar-Kami ń ska et al.,…”
BackgroundDetecting Markers of Therapy-Induced Senescence in Cancer Cells
Fan, D. N.-Y., & Schmitt, C. A. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6670-7_4 · Cited by 11 · see citing works
“This is of particular importance, since the largely NF-κB-driven pro-inflammatory and matrix-remodeling components of the SASP may affect adjacent (pre-)tumor cells, profoundly alter the tumor microenvironment and attract host immune cells (1-4, 12, 19, 21, 22).”
BackgroundStem Cell Biology in Health and Disease
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Arginine methylation in cancer: mechanisms and therapeutic implications
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“Additionally, previous studies have shown that high CXCR2 levels are associated with senescence in premalignant lesions and that the loss of CXCR2 expression contributes to reducing the severity of the arrest via the activation of the p53 pathway (47,48).”
BackgroundLin, X., Zhang, H., Liu, J., Wu, C., McDavid, A., Boyce, B. F., & Xing, L. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.806528 · Cited by 6 · see citing works
“, 2008) and promotes cellular senescence via Rb/p16 and p53/ p21 signaling pathways (Acosta et al., 2008; Acosta and Gil, 2009).”
BackgroundChemokines Effective on Platelet Functions
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- Authors
- Acosta, J. C., Loghlen, A., Banito, A., Raguz, S., & Gil, J.
- Affiliations
- Imperial College London (GB)
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2008-10
- Volume
- 7
- Issue
- 19
- Pages
- 2956-2959
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W1970733036
- Cited by
- 106
- References
- 21
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 2 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 12 · 2015: 5 · 2014: 8 · 2013: 12 · 2012: 6
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- China Scholarship Council
- Medical Research Council
- Fundação para a Ciência e a Tecnologia
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- cellular senescence, CXCR2, chemokines, senescence-associated secretory phenotype, interleukin-8, CXCL1, p53 pathway, paracrine signaling, autocrine signaling, secreted factors, tumor suppression, aging, plasminogen activator inhibitor-1, IGFBP7, interleukin-6
- MeSH terms
- Animals, DNA Damage, Humans, Ligands, Models, Biological, Interleukin-8, Cellular Senescence, Receptors, Interleukin-8B, Chemokine CXCL1
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