Abstract 2616: Thioredoxin reductase 1 modulates methylseleninic acid-induced redox status effects in A549 human lung cancer cells

Abstract

Abstract Thioredoxin reductase (TR1) is a selenoprotein that is involved in cellular redox status control and deoxyribonucleotide biosynthesis. Many cancers, including lung, overexpress TR1, making it a potential cancer therapy target. TR1 is hypothesized to be involved in the mechanism of selenium in cancer etiology. Also of interest is the selenocompound methylseleninic acid (MSA). MSA is a known substrate of TR1 and previous work has shown that TR1 knockdown enhances MSA toxicity and redox status effects in human colon cancer cells compared to those with endogenous TR1 levels. However, it is unknown if TR1 knockdown produces similar effects of MSA in human lung cancer cells. To further elucidate the role of TR1 in the mechanism of MSA in lung cancer, a lentiviral microRNA delivery system to knockdown TR1 expression in A549 adenocarcinoma cells (A549 miR-TR1) was utilized. Redox status after 24 hr MSA treatment was assessed by measuring reactive oxygen species (ROS) generation, mitochondrial membrane depolarization, and total glutathione (GSH) concentration. Although the toxicity of MSA was not increased in A549 miR-TR1 cells at 24 hrs, changes in redox status parameters were observed. TR1 knockdown alone had no effect on mitochondrial membrane depolarization or ROS, but did increase ROS and mitochondrial membrane depolarization generated by MSA. Total GSH concentration was increased by TR1 knockdown alone, the majority of which was reduced glutathione. MSA decreased total GSH concentration and TR1 knockdown further enhanced this MSA-induced attenuation in total GSH. These results indicate the ability of TR1 to modulate the redox status effects of MSA in human lung cancer cells. Potential use of MSA as a cancer treatment in combination with TR1 inhibitors is also of interest. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2616.