Inhibition of ATP citrate lyase (ACLY) protects airway epithelia from PM2.5-induced epithelial-mesenchymal transition

Abstract

Epidemiological studies have associated ambient fine particulate matter (PM2.5) exposure with lung cancer, in which epithelial-mesenchymal transition (EMT) is an initial process. Thus, it is important to identify the key molecule or pathway involved in the PM2.5 induced EMT. Human bronchial epithelial (HBE) cells were exposed to PM2.5 (100 or 500 μg/ml) for 30 passages and analyzed by metabolomics to identify the alteration of metabolites related to PM2.5 exposure. The expression levels of EMT markers were evaluated by qRT-PCR and Western blot assays in HBE cells and murine lung tissues. Reduced epithelial markers, increased mesenchymal markers expression levels and increased capacity of metastasis were observed in PM2.5-exposed HBE cells. Metabolomics analysis suggested upregulation of citrate acid with fold change (FC) of 2.89 or 4.18 in 100 or 500 μg/ml PM2.5 treated HBE cells. For both of the in vitro and in vivo study, the up-regulation of ATP citrate lyase (ACLY) was confirmed following PM2.5 exposure. Importantly, ACLY knockdown in HBE cells reversed EMT, migration and invasion capacities in HBE cells induced by PM2.5. Taken together, our data suggest that inhibition of ACLY demonstrates a protection against PM2.5-induced EMT, providing a concern on the molecular mechanisms of PM2.5-associated pulmonary disorders.