A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Juan Carlos Acosta,Ana Banito,Torsten Wuestefeld,Athena Georgilis,Peggy Janich,Jennifer P. Morton,Dimitris Athineos,Tae-Won Kang,Felix Lasitschka,Mindaugas Andrulis,Gloria Pascual,Kelly J. Morris,Sadaf Khan,Hong Jin,Gopuraja Dharmalingam,Ambrosius P. Snijders,Thomas L. Carroll,David Capper,Catrin Pritchard,Gareth J. Inman,Thomas Longerich,Owen J. Sansom,Salvador Aznar Benitah,Lars Zender,Jesús Gil +24 more
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TLDR
It is demonstrated that the SASP can cause paracrine senescence and impact on tumour suppression andSenescence in vivo and TGF-β ligands play a major role by regulating p15INK4b and p21CIP1.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 p15(INK4b) and p21(CIP1). 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.read more
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Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance.
Fei Chen,Qilai Long,Da Fu,Dexiang Zhu,Yan Ji,Liu Han,Boyi Zhang,Qixia Xu,Bingjie Liu,Yan Li,Shanshan Wu,Chen Yang,Min Qian,Jianmin Xu,Suling Liu,Liu Cao,Y. Eugene Chin,Eric Lam,Jean-Philippe Coppe,Yu Sun,Yu Sun,Yu Sun +21 more
TL;DR: It is shown that genotoxic stress induces senescence in human stromal cells, which in turn secrete serine protease inhibitor Kazal type 1 (SPINK1) and promote acquired resistance of cancer cells via EGFR-mediated paracrine signaling.
Journal ArticleDOI
Cellular senescence and cancer: Focusing on traditional Chinese medicine and natural products.
Yiman Liu,Shenshen Yang,Kailong Wang,Jia Lu,Xiaomei Bao,Rui Wang,Yuling Qiu,Tao Wang,Haiyang Yu +8 more
TL;DR: The recent research progress on the main compounds derived from TCM and natural products that play anti‐cancer roles by inducing cell senescence is systematically reviewed, aiming to provide a reference for the clinical treatment of pro‐senescent cancer.
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Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation
TL;DR: The role of theNLRP3 inflammasome in the pathogenesis of metabolic disease that is associated with mitochondrial and oxidative stress is highlighted and the recently emerging noncanonical and alternative pathways to NLRP3 activation are explored.
Journal ArticleDOI
Galactose-modified duocarmycin prodrugs as senolytics.
Ana Guerrero,Romain Guiho,Nicolás Herranz,Anthony G. Uren,Dominic J. Withers,Juan Pedro Martinez-Barbera,Lutz F. Tietze,Jesús Gil +7 more
TL;DR: A case is made for testing the potential of galactose‐modified duocarmycin prodrugs to treat senescence‐related pathologies following evidence that the selective elimination of senescent cells can be effective on the treatment of many age‐related diseases.
Journal ArticleDOI
Cellular senescence as a potential mediator of COVID-19 severity in the elderly
Jamil Nehme,Jamil Nehme,Michela Borghesan,Sebastian Mackedenski,Thomas G. Bird,Thomas G. Bird,Marco Demaria +6 more
TL;DR: How cellular senescence—a state of stable growth arrest characterized by pro‐inflammatory and pro‐disease functions—can hypothetically be a contributor to COVID‐19 pathogenesis, and a potential pharmaceutical target to alleviate disease severity is discussed.
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