A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory
Eric H Bent1, Luke A Gilbert1, Michael T Hemann1
1The David H. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
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.
Insights
Chemotherapy can cause inflammation by damaging normal cells. This study reveals how endothelial cells limit this response, preventing chronic inflammation and preserving tissue homeostasis during cancer treatment.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Cancer therapies damage both malignant and nonmalignant cells, altering the tumor microenvironment.
- Therapy-induced damage can lead to cellular senescence and inflammation, potentially promoting cancer.
- Mechanisms regulating the resolution of these damage responses to maintain tissue homeostasis are poorly understood.
Purpose of the Study:
- To investigate the regulation of acute chemotherapy-induced secretory responses.
- To understand how endothelial cells manage senescence-associated inflammation.
- To identify mechanisms preventing chronic inflammation post-chemotherapy.
Main Methods:
- Utilized tissue-specific knockout mice.
- Investigated the role of endothelial Interleukin-6 (IL-6) in chemoresistance.
- Analyzed doxorubicin-induced IL-6 release via reactive oxygen species (ROS) and p38 activation.
- Examined the regulation of senescence-associated inflammation by PI3K/AKT/mTOR signaling.
Main Results:
- Chemotherapy induces a self-limiting secretory response in endothelial cells despite causing senescence.
- Endothelial IL-6 production promotes chemoresistance.
- Doxorubicin triggers acute IL-6 release through ROS-mediated p38 activation.
- Endothelial cells suppress senescence-associated inflammation by down-regulating PI3K/AKT/mTOR signaling.
Conclusions:
- Endothelial cells possess a mechanism to restrain damage-associated secretory responses, preventing chronic inflammation.
- This restraint is crucial for preserving tissue homeostasis during cancer therapy.
- Down-regulation of PI3K/AKT/mTOR signaling is key to limiting senescence-associated inflammation.
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