镉 (Cd) 暴露会显着增加患肺癌的风险。癌症（包括肺癌）对谷氨酰胺的需求正在增加。在这项研究中，我们研究了谷氨酰胺代谢在镉诱导的细胞生长和迁移中的作用。首先，我们发现2μM Cd处理上调A549细胞中ASCT2（丙氨酸、丝氨酸、半胱氨酸偏好转运蛋白2）和ASNS（天冬酰胺合成酶）的表达，同时下调线粒体谷氨酰胺酶GLS1。用 0.5 和 1mgCd/kg 体重处理的雄性 BALB/c 小鼠也获得了相同的结果。随后，谷氨酰胺剥夺和 siASCT2 转染均表明谷氨酰胺在镉诱导的细胞生长和迁移中发挥作用。此外，使用内质网 (ER) 应激抑制剂 4-PBA (5mM)、ER 应激诱导剂 Tm (0.1μg/ml)、siHMGA2 和过表达 HMGA2 质粒，我们证明 ER 应激/HMGA2轴参与诱导 ASCT2 和 ASNS，同时抑制 GLS1。此外，使用 HMGA2 抗体进行的染色质免疫沉淀测定显示 HMGA2 与 ASCT2、ASNS 和 GLS1 基因的启动子序列直接结合。最后，双荧光素酶报告基因测定确定HMGA2增加ASCT2和ASNS的转录，同时抑制GLS1的转录。总体而言，我们发现内质网应激诱导的 HMGA2 通过 ASCT2、ASNS 和 GLS1 的转录调节来控制谷氨酰胺代谢，从而在低浓度 Cd 暴露期间加速细胞生长和迁移。这项研究创新性地揭示了镉诱导细胞生长的机制，为通过谷氨酰胺代谢预防镉毒性提供了新的视角。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Cadmium (Cd) exposure significantly increases the risk of lung cancer. The demand for glutamine is increasing in cancers, including lung cancer. In this study, we investigated the role of glutamine metabolism in Cd-induced cell growth and migration. Firstly, we found that 2 μM Cd-treatment up-regulated the expression of ASCT2 (alanine, serine, cysteine-preferring transporter 2) and ASNS (asparagine synthetase) while downregulating mitochondrial glutaminase GLS1 in A549 cells. The same results were obtained in male BALB/c mice treated with 0.5 and 1 mg Cd/kg body weight. Subsequently, both glutamine deprivation and transfection with siASCT2 revealed that glutamine played a role in Cd-induced cell growth and migration. Furthermore, using 4-PBA (5 mM), an inhibitor of endoplasmic reticulum (ER) stress, Tm (0.1 μg/ml), an inducer of ER stress, siHMGA2, and over-expressing HMGA2 plasmids we demonstrated that ER stress/HMGA2 axis was involved in inducing ASCT2 and ASNS, while inhibiting GLS1. Additionally, the chromatin immunoprecipitation assay using an HMGA2 antibody revealed the direct binding of the HMGA2 to the promoter sequences of the ASCT2, ASNS, and GLS1 genes. Finally, dual luciferase reporter assay determined that HMGA2 increased the transcription of ASCT2 and ASNS while inhibiting the transcription of GLS1. Overall, we found that ER stress-induced HMGA2 controls glutamine metabolism by transcriptional regulation of ASCT2, ASNS and GLS1 to accelerate cell growth and migration during exposure to Cd at low concentrations. This study innovatively revealed the mechanism of Cd-induced cell growth which offers a fresh perspective on preventing Cd toxicity through glutamine metabolism.Copyright © 2024 Elsevier B.V. All rights reserved.