TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5)

Abstract

Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with a number of pathological respiratory diseases, such as bronchitis, asthma, and chronic obstructive pulmonary disease, which share the common feature of airway inflammation induced by particle exposure. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is crucial for the study of PM2.5 toxicity. In the current study, we found that exposing human bronchial epithelial cells (immortalized Beas-2B cells and primary cells) to PM2.5 collected in the winter in Wuhan, a city in southern China, induced a significant upregulation of VEGFA (vascular endothelial growth factor A) production, a signaling event that typically functions to control chronic airway inflammation and vascular remodeling. Further investigations showed that macroautophagy/autophagy was induced upon PM2.5 exposure and then mediated VEGFA upregulation by activating the SRC (SRC proto-oncogene, non-receptor tyrosine kinase)-STAT3 (signal transducer and activator of transcription 3) pathway in bronchial epithelial cells. By exploring the upstream signaling events responsible for autophagy induction, we revealed a requirement for TP53 (tumor protein p53) activation and the expression of its downstream target DRAM1 (DNA damage regulated autophagy modulator 1) for the induction of autophagy. These results thus extend the role of TP53-DRAM1-dependent autophagy beyond cell fate determination under genotoxic stress and to the control of proinflammatory cytokine production. Moreover, PM2.5 exposure strongly induced the activation of the ATR (ATR serine/threonine kinase)-CHEK1/CHK1 (checkpoint kinase 1) axis, which subsequently triggered TP53-dependent autophagy and VEGFA production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure.

Selective degradation of IKKα by autophagy is essential for arsenite-induced cancer cell apoptosis

“…The detected whether IKKα is required for CHK1/p53 interaction in the arsenite response, HepG2 cells were transfected with IKKα siRNA or the control siRNA, and then reciprocal IPs were performed to detect the changes on CHK1/p53 interaction with or without IKKα expression. Cellular protein preparation and immunoblot assays were performed as described previously 17,18 .…”

Function of PM2.5 in the pathogenesis of lung cancer and chronic airway inflammatory diseases (Review)

“…Previous research has focused on the epidemiology and toxicology of PM2.5; however, more recent research has investigated the function that PM2.5 serves in the pathogenesis of respiratory diseases. PM2.5-induced epigenetic changes, including microRNA dysregulation (37) and DNA methylation (46), microenvironment alteration (53), cell autophagy and apoptosis (67,68), may result in oncogene activation and tumor suppressor gene inactivation in lung cancer (Fig. 1).…”

“…Furthermore, autophagy is able to regulate apoptosis by altering the level and activity of caspase proteins (66). PM2.5 exposure may induce macrophage autophagy and mediate the Src/STAT-3 signaling pathway to increase the expression of VEGF-A, an important pro-angiogenic factor (67). It has also been suggested that the phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin kinase signaling pathway may serve an important function in the autophagy of BEAS-2B cells exposed to PM2.5 (68).…”

Neoantigens in Chronic Obstructive Pulmonary Disease and Lung Cancer: A Point of View

“…Exposing human bronchial epithelial cells to high levels of particulate matter 2.5 (PM2.5; the mass per cubic meter of air of particles with a size of less than 2.5 μm) induces significant upregulation of vascular endothelial growth factor A (VEGA) production. Macroautophagy/autophagy is induced upon PM2.5 exposure and then mediates VEGA upregulation by activating the SRC‐CTA3 pathway in bronchial epithelial cells…”