Abstract 938: Activation of ATR/CHK1 checkpoint is critical for mediating p53-dependent autophagy and pro-inflammatory VEGF production in human bronchial epithelial cells under fine particulate matters (PM2.5) exposure

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Abstract The epidemiological and clinical studies have increasingly shown that fine particulate matters (PM2.5) exposure is associated with exacerbation of airway inflammation, which might results in the occurrence of lung cancer. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is a crucial issue for the study of PM2.5 toxicity. In the current study, we found that exposure of human bronchial epithelial cells (Beas-2B) to the winter PM2.5 collected in Wuhan, the south city of China, induced an significant up-regulation of VEGF production, a typical signaling event functionally in controlling chronic airway inflammation and vascular remodeling. Further investigations showed that autophagy was induced upon PM2.5 exposure and then mediated VEGF up-regulation by activating Src/STAT3 pathway in the Beas-2B cells. When exploring the upstream signaling events responsible for autophagy induction, we disclosed the requirement of p53 activation and its downstream target DRAM expression for the induction of autophagy, which results thus have extended the role of p53/DRAM-dependent autophagy beyond cell fate determination under genotoxic stresses and to the control of pro-inflammatory cytokine production. Moreover, PM2.5 exposure strongly induced activation of ATR/CHK1 axis, which subsequently triggered p53-dependent autophagy and VEGF production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genome integrity and the airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure. Citation Format: Lun Song. Activation of ATR/CHK1 checkpoint is critical for mediating p53-dependent autophagy and pro-inflammatory VEGF production in human bronchial epithelial cells under fine particulate matters (PM2.5) exposure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 938.