Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, we assessed the role of ANGPTL4 in lung carcinogenesis under nickel exposure and investigated the effects of the antidiabetic drug metformin on ANGPTL4 expression and lung cancer chemoprevention. Our results showed that ANGPTL4 is increased in NiCl2-treated lung cells in a dose- and time-course manner. The expression of ANGPTL4 and HIF-1 alpha induced by NiCl2 were significantly repressed after metformin treatment. The downregulation of HIF-1 alpha expression by ROS savenger and HIF-1 alpha inhibitor or knockdown by lentiviral shRNA infection diminished NiCl2-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl2-induced HIF-1 alpha hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1 alpha accumulation that is caused by nickel in lung cells may be one mechanism by which nickel exposure contributes to lung cancer progression. Additionally, metformin has the ability to prevent NiCl2-induced ANGPTL4 through inhibiting HIF-1 alpha expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent.
