1. mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis.
- Author
-
Iglesias-Bartolome R, Patel V, Cotrim A, Leelahavanichkul K, Molinolo AA, Mitchell JB, and Gutkind JS
- Subjects
- Animals, Carcinoma, Squamous Cell enzymology, Carcinoma, Squamous Cell pathology, Cell Compartmentation drug effects, Cell Compartmentation radiation effects, Cell Death drug effects, Cell Death radiation effects, Cell Proliferation drug effects, Cell Proliferation radiation effects, Cells, Cultured, Clone Cells, Epithelial Cells drug effects, Epithelial Cells enzymology, Epithelial Cells radiation effects, Head and Neck Neoplasms enzymology, Head and Neck Neoplasms pathology, Humans, Keratinocytes drug effects, Keratinocytes enzymology, Keratinocytes pathology, Keratinocytes radiation effects, Mice, Mouth Mucosa drug effects, Mouth Mucosa pathology, Mouth Mucosa radiation effects, Mucositis enzymology, Mucositis pathology, Oxidative Stress drug effects, Oxidative Stress radiation effects, Radiation Injuries enzymology, Radiation Injuries pathology, Radiation, Ionizing, Sirolimus pharmacology, Stem Cells drug effects, Stem Cells enzymology, Stem Cells radiation effects, Superoxide Dismutase metabolism, TOR Serine-Threonine Kinases metabolism, Cellular Senescence drug effects, Cellular Senescence radiation effects, Cytoprotection drug effects, Cytoprotection radiation effects, Epithelial Cells pathology, Mucositis prevention & control, Radiation Injuries prevention & control, Stem Cells pathology, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence. This protective effect of rapamycin is mediated by the increase in expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress. mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF