Abstract
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-1α induced by NiCl2 were significantly repressed after metformin treatment. The downregulation of HIF-1α expression by ROS savenger and HIF-1α inhibitor or knockdown by lentiviral shRNA infection diminished NiCl2-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl2-induced HIF-1α hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1α 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-1α expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent.
Highlights
Nickel (Ni) compounds are common environmental pollutants, the sources of which include metallurgy waste air, burning of fossil fuels, and cigarette smoke, and they are recognized as a group 1 human carcinogen by the International Agency for Research on Cancer [1]
Most of the studies have reported that Angiopoietin-like protein 4 (ANGPTL4) plays major roles in cancer progression and development and it is involved in the regulation of energy metabolism, angiogenesis, metastasis, and
Most of the studies have reported that ANGPTL4 plays major roles in cancer progression and development and it is involved in the regulation of energy metabolism, angiogenesis, metastasis, and anoikis resistance
Summary
Nickel (Ni) compounds are common environmental pollutants, the sources of which include metallurgy waste air, burning of fossil fuels, and cigarette smoke, and they are recognized as a group 1 human carcinogen by the International Agency for Research on Cancer [1]. Previous in vitro and in vivo studies on nickel toxicity and carcinogenesis have demonstrated its ability to induce DNA damage, epigenetic alterations, disruption of cellular iron homeostasis, and generation of reactive oxygen species (ROS), nickel has been found to be only weakly mutagenic. Nickel acts as an imitator of hypoxia, with the resulting hypoxia responding to activation and hypoxia-inducible factor (HIF) accumulation, which inhibits the activity of prolyl hydroxylases and disrupts the degradation of HIFs [6,7]. Our previous studies have indicated that nickel exposure results in ROS production, which contributes to epithelial–mesenchymal transition (EMT) and the activation of autophagy [8,9]. We propose a therapeutic strategy against HIF-1-induced carcinogenesis due to nickel exposure
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