NOTCH signaling promotes survival of irradiated basal airway stem cells.

NOTCH signaling promotes survival of irradiated basal airway stem cells. Am J Physiol Lung Cell Mol Physiol. 2019 Jul 19;: Authors: Giuranno L, Wansleeben C, Iannone R, Arathoon L, Hounjet J, Groot AJ, Vooijs M Abstract Radiation-induced lung injury to normal airway epithelium is a frequent side-effect and dose-limiting factor in radiotherapy of tumors in the thoracic cavity. NOTCH signaling plays key roles in self-renewal and differentiation of upper airway basal lung stem cells during development and the NOTCH pathway is frequently deregulated in lung cancer. In preclinical lung cancer models, NOTCH inhibition was shown to improve the radiotherapy response by targeting tumor stem cells but the effects in combination with irradiation on normal lung stem cells are unknown. NOTCH/gamma-secretase inhibitors are potent clinical candidates to block NOTCH function in tumors but their clinical implementation has been hampered by normal tissue side effects. Here we show that NOTCH signaling is active in primary human- and murine-derived airway epithelial stem cell models and when combined with radiation NOTCH inhibition provokes a decrease in S-phase and increase in G1 arrest. We show that NOTCH inhibition in irradiated lung basal stem cells leads to a more potent activation of the DNA damage checkpoint kinases pATM and pCHK2 and results in an increased level of residual 53BP1 foci in irradiated lung basal stem cells reducing their capacity...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research