Inhibition of ATP citrate lyase (ACLY) protects airway epithelia from PM_2.5-induced epithelial-mesenchymal transition

Epidemiological studies have associated ambient fine particulate matter (PM_2.5) 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 PM_2.5 induced EMT. Human bronchial epithelial (HBE) cells were exposed to PM_2.5 (100 or 500 μg/ml) for 30 passages and analyzed by metabolomics to identify the alteration of metabolites related to PM_2.5 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 PM_2.5-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 PM_2.5 treated HBE cells. For both of the in vitro and in vivo study, the up-regulation of ATP citrate lyase (ACLY) was confirmed following PM_2.5 exposure. Importantly, ACLY knockdown in HBE cells reversed EMT, migration and invasion capacities in HBE cells induced by PM_2.5. Taken together, our data suggest that inhibition of ACLY demonstrates a protection against PM_2.5-induced EMT, providing a concern on the molecular mechanisms of PM_2.5-associated pulmonary disorders.