A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses.
A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses.
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DOI：
10.1101/gad.284851.116
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发表时间：
2016-08-15
影响因子：
10.5
通讯作者：
Hemann MT
中科院分区：
文献类型：
--
作者：
Bent EH;Gilbert LA;Hemann MT
Bent等表明，内皮细胞产生IL-6促进化学抗性，多柔比星通过活性氧介导的p38活化诱导急性IL-6释放。内皮细胞通过下调PI 3 K/AKT/mTOR信号转导抑制衰老相关炎症，并且该途径的再激活恢复衰老相关炎症。癌症治疗的目标是被多种非恶性基质细胞包围的恶性细胞。治疗诱导的正常细胞损伤可以改变肿瘤微环境，导致细胞衰老并激活促癌炎症。然而，如何调节这些损伤反应（诱导和解决），以保持组织的稳态和预防慢性炎症知之甚少。在这里，我们详细介绍了急性化疗诱导的分泌反应，是自限性的体外和体内，尽管诱导细胞衰老。我们使用组织特异性基因敲除小鼠来证明促炎细胞因子IL-6的内皮产生促进化疗耐药性，并表明化疗阿霉素通过活性氧介导的p38体外活化诱导急性IL-6释放。多柔比星引起内皮衰老，但令人惊讶的是，没有典型的衰老分泌反应。我们发现，内皮细胞通过下调PI 3 K/AKT/mTOR信号转导抑制衰老相关炎症，并且该途径的重新激活恢复衰老相关炎症。因此，我们描述了一种机制，通过这种机制，损伤相关的旁分泌反应受到抑制，以保持组织的稳态，防止慢性炎症。
Bent et al. show that endothelial production of IL-6 promotes chemoresistance, and doxorubicin induces acute IL-6 release through reactive oxygen species-mediated p38 activation. Endothelial cells repress senescence-associated inflammation through the downregulation of PI3K/AKT/mTOR signaling, and reactivation of this pathway restores senescence-associated inflammation. 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.
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影响因子：
64.8
作者：
Karin M;Clevers H
通讯作者：
Clevers H
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars