Jui‐Chin WangShih‐Yin ChenMeilin WangJiunn‐Liang KoChieh‐Lin WuChing‐Chung ChenHui‐Wen LinYuan‐Yen Chang2026-01-292026-01-292019-02-0610.1002/tox.22731https://scholars.csmu.edu.tw/handle/123456789/3822<jats:title>Abstract</jats:title><jats:p>Prospective cohort studies have indicated that a highly nickel‐polluted environment may severely affect human health, resulting in such conditions as respiratory tract cancers. Such exposure can trigger vascular endothelial growth factor (VEGF) expression. However, the signal transduction pathways leading to VEGF induction by nickel compounds are not well understood. This study revealed the occurrence of VEGF induction in human non‐small‐cell lung cancer H460 cells exposed to NiCl<jats:sub>2</jats:sub>. Moreover, exposing H460 cells to NiCl<jats:sub>2</jats:sub> activated extracellular signal‐regulated protein kinase (ERK), nuclear factor kappa B (NFκB), and protein kinase B (Akt) as well as downregulated AMP activated protein kinase (AMPK) expression. The mitogen‐activated protein kinase (MAPK) and ERK inhibitor significantly blocked NiCl<jats:sub>2</jats:sub>‐induced ERK activation and VEGF production. Pretreating H460 cells with a PI3K/Akt inhibitor substantially inhibited NiCl<jats:sub>2</jats:sub>‐induced VEGF expression and reduced Akt, ERK, and NFκB phosphorylation. Furthermore, 5‐aminoimidazole‐4‐carboxamide ribonucleoside‐induced AMPK activation improved VEGF expression in NiCl<jats:sub>2</jats:sub>‐treated H460 cells significantly. These results indicate that NiCl<jats:sub>2</jats:sub> induces VEGF production through Akt, ERK, NFκB activation and AMPK suppression and mediates various types of pathophysiological angiogenesis.</jats:p>[SDGs]SDG3journal-article