D-Limonene Inhibits the Occurrence and Progression of LUAD by Suppressing Lipid Metabolism Dysregulation Induced by PM2.5 Exposure

Abstract

Background: PM2.5 exposure is associated with lung adenocarcinoma (LUAD), but the mechanism is unclear. The lack of understanding impedes our effort on prevention. This study examined a possible mechanism of lung cancer caused by PM2.5 exposure, and aimed to find a potential intervention for people living in PM2.5 polluted regions.Methods: PM2.5 was collected near South-North elevated way in Shanghai city. Lung adenocarcinoma cells, pulmonary epithelial cell and mice were exposed to PM2.5 or D-limonene for 48h and two month separately. Cell morphology, abilities of invasion, migration and proliferation, pulmonary fibrosis level were assessed. Lipid metabolism changes were also studied in 11,564 lung cancer patients.Results: PM2.5 exposure induced accumulation of lipid droplets in LUAD cells which was accompanied by increased malignant cellular behaviors and disrupted lipid metabolism. PM2.5 exposure of LUAD led to cleaved N-SREBP1 translocation from the cytoplasm to nucleus, which upregulated the expression of FASN and ACACA. These changes increased lipid accumulation in LUAD. D-limonene, a natural monoterpene, was found to inhibit the changes in lipid metabolism through upregulating the expression of miR-195, a reported tumor suppressor that inhibited the expression of SREBP1, FASN and ACACA specifically induced by PM2.5 exposure. Same changes were also observed in normal lung epithelial cells and normal lung tissue from mice after PM2.5 exposure, and the changes were inhibited by D-limonene treatment. Furthermore, in a cohort of 11,564 lung cancer patients, significant lipid metabolism disorders were observed in high, compared to low, PM2.5 polluted areas, and a small human intervention trial showed that serum miR-195 was upregulated after oral intake of D-limonene.Conclusion: Our study reveals a potential intervention target for LUAD that is related to PM2.5 exposure-induced lipid metabolism disturbance and that D-limonene may inhibit the disruption through the upregulation of miR-195, which suggests a novel low-cost preventive intervention for people living in PM2.5 polluted regions.