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A complex secretory program orchestrated by the inflammasome controls paracrine senescence

Title: A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Authors: Acosta, JC
Banito, A
Wuestefeld, T
Georgilis, A
Janich, P
Morton, JP
Athineos, D
Kang, T-W
Lasitschka, F
Andrulis, M
Pascual, G
Morris, KJ
Khan, S
Jin, H
Dharmalingam, G
Snijders, AP
Carroll, T
Capper, D
Pritchard, C
Inman, GJ
Longerich, T
Sansom, OJ
Aznar Benitah, S
Zender, L
Gil, J
Item Type: Journal Article
Abstract: Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15INK4b and p21CIP1. Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.
Issue Date: 1-Aug-2013
Date of Acceptance: 13-May-2013
URI: http://hdl.handle.net/10044/1/76687
DOI: 10.1038/ncb2784
ISSN: 1465-7392
Publisher: Nature Research
Start Page: 978
End Page: U221
Journal / Book Title: Nature Cell Biology
Volume: 15
Issue: 8
Copyright Statement: © 2013 Macmillan Publishers Limited. All rights reserved. The final publication is available at Springer via https://doi.org/10.1038/ncb2784
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
DIPLOID CELL STRAINS
NF-KAPPA-B
PANCREATIC-CANCER
TGF-BETA
TUMOR PROGRESSION
GROWTH
TUMORIGENESIS
P16(INK4A)
EXPRESSION
P53
Animals
Cell Line, Tumor
Cellular Senescence
Colonic Neoplasms
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Inflammasomes
Interleukin-1
Mice
Models, Animal
Paracrine Communication
Protein Binding
Signal Transduction
Transforming Growth Factor beta1
Cell Line, Tumor
Animals
Humans
Mice
Colonic Neoplasms
Interleukin-1
Immunohistochemistry
Models, Animal
Cell Aging
Paracrine Communication
Signal Transduction
Gene Expression Regulation, Neoplastic
Protein Binding
Transforming Growth Factor beta1
Inflammasomes
Science & Technology
Life Sciences & Biomedicine
Cell Biology
DIPLOID CELL STRAINS
NF-KAPPA-B
PANCREATIC-CANCER
TGF-BETA
TUMOR PROGRESSION
GROWTH
TUMORIGENESIS
P16(INK4A)
EXPRESSION
P53
Developmental Biology
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2013-06-16
Appears in Collections:Institute of Clinical Sciences