A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses
Name
Bent-A senescence secreto.pdf
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984.75 KB
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Author(s)
Bent, Eric H
Gilbert, Luke Andrew
Hemann, Michael
Date Issued
August 2016
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory Press
Citation
Bent, Eric H., Luke A. Gilbert, and Michael T. Hemann. “A Senescence Secretory Switch Mediated by PI3K/AKT/mTOR Activation Controls Chemoprotective Endothelial Secretory Responses.” Genes & Development 30.16 (2016): 1811–1821.
Version
Final published version
Abstract
Cancer therapy targets malignant cells that are surrounded by a diverse complement of nonmalignant stromal cells. Therapy-induced damage of normal cells can alter the tumor microenvironment, causing cellular senescence and activating cancer-promoting inflammation. However, how these damage responses are regulated (both induced and resolved) to preserve tissue homeostasis and prevent chronic inflammation is poorly understood. Here, we detail an acute chemotherapy-induced secretory response that is self-limiting in vitro and in vivo despite the induction of cellular senescence. We used tissue-specific knockout mice to demonstrate that endothelial production of the proinflammatory cytokine IL-6 promotes chemoresistance and show that the chemotherapeutic doxorubicin induces acute IL-6 release through reactive oxygen species-mediated p38 activation in vitro. Doxorubicin causes endothelial senescence but, surprisingly, without a typical senescence secretory response. We found that endothelial cells repress senescence-associated inflammation through the down-regulation of PI3K/AKT/mTOR signaling and that reactivation of this pathway restores senescence-associated inflammation. Thus, we describe a mechanism by which damage-associated paracrine secretory responses are restrained to preserve tissue homeostasis and prevent chronic inflammation.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial 4.0 International
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DOI of Published Version
https://doi.org/10.1101/gad.284851.116
