Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Ecotoxicol Environ Saf. 2022 May 1;236:113461. doi: 10.1016/j.ecoenv.2022.113461. Epub 2022 Apr 8.
Nickel (Ni) compounds is recognized industrial carcinogen, which could increase the risk of lung cancer in Ni refineries workers. However, the underlying carcinogenic mechanism still remains to elucidate. Metformin has shown the anticancer properties through suppressing aerobic glycolysis. In the present study, we evaluated the effect of Ni-refining fumes exposure on aerobic glycolysis and the role of AMPK/GOLPH3, as well as how metformin alleviated nickel-induced aerobic glycolysis in vitro and vivo. Firstly, Beas-2B cells were exposed to different concentrations of Ni-refining fumes and pretreated with metformin (activation of AMPK), compound C (AMPK inhibitor) in vitro. Our findings indicated that Ni fumes expose evoked aerobic glycolysis by AMPK/GOLPH3, while metformin attenuated Ni particles-promoted GOLPH3-mediated aerobic glycolysis by p-AMPK expression increase. Then Mito-TEMPT (a mitochondria-targeted antioxidant) and lipopolysaccharide (LPS, ROS activator) were pretreated to affect ROS production in Beas-2B cells. Ni-induced ROS prevented AMPK activation. Moreover, C57BL/6 mice were exposed to 2 mg/kg Ni by non-exposed endotracheal instillation and metformin (100, 200 and 300 mg/kg) via oral gavage for 4 weeks. The effects of AMPK/GOLPH3 axis on Ni-induced aerobic glycolysis were assessed. The results indicated that metformin decreased the protein levels of GOLPH3, LDHA, HK2, MCT-4 and improved p-AMPK expression. Thus, our findings demonstrated metformin antagonized Ni-refining fumes-caused aerobic glycolysis via AMPK/GOLPH3.
镍（Ni）化合物被认为是工业致癌物质，可增加镍精炼厂工人患肺癌的风险。然而，其潜在的致癌机制仍有待阐明。二甲双胍通过抑制有氧糖酵解显示出抗癌特性。在本研究中，我们评估了 Ni 精炼烟尘暴露对有氧糖酵解的影响，以及 AMPK/GOLPH3 的作用，以及二甲双胍如何在体外和体内缓解镍诱导的有氧糖酵解。首先，将 Beas-2B 细胞暴露于不同浓度的 Ni 精炼烟尘中，并在体外用二甲双胍（激活 AMPK）、化合物 C（AMPK 抑制剂）预处理。我们的研究结果表明，Ni 烟尘暴露通过 AMPK/GOLPH3 引起有氧糖酵解，而二甲双胍通过增加 p-AMPK 表达减弱 Ni 颗粒促进的 GOLPH3 介导的有氧糖酵解。然后，用 Mito-TEMPT（一种线粒体靶向抗氧化剂）和脂多糖（LPS，ROS 激活剂）预处理以影响 Beas-2B 细胞中的 ROS 产生。Ni 诱导的 ROS 阻止了 AMPK 的激活。此外，通过非暴露气管内滴注将 C57BL/6 小鼠暴露于 2mg/kg Ni，并用二甲双胍（100、200 和 300mg/kg）通过口服灌胃 4 周。评估了 AMPK/GOLPH3 轴对 Ni 诱导的有氧糖酵解的影响。结果表明，二甲双胍降低了 GOLPH3、LDHA、HK2、MCT-4 的蛋白水平，并改善了 p-AMPK 的表达。因此，我们的研究结果表明，二甲双胍通过 AMPK/GOLPH3 拮抗 Ni 精炼烟尘引起的有氧糖酵解。
