Therapeutic Discovery The Relationship of Thioredoxin-1 and Cisplatin Resistance: Its Impact on ROS and Oxidative Metabolism in Lung Cancer Cells

Elimination of cisplatin-resistant lung cancer cells remains a major obstacle. We have shown that cisplatinresistant tumorshavehigher reactiveoxygen species (ROS) levels and canbe exploited for targeted therapy.Here, we show that increased secretion of the antioxidant thioredoxin-1 (TRX1) resulted in lowered intracellular TRX1 and contributed to higher ROS in cisplatin-resistant tumors in vivo and in vitro. By reconstituting TRX1 protein in cisplatin-resistant cells,we increased sensitivity to cisplatin butdecreased sensitivity to elesclomol (ROS inducer). Conversely, decreased TRX1 protein in parental cells reduced the sensitivity to cisplatin but increased sensitivity to elesclomol. Cisplatin-resistant cells had increased endogenous oxygen consumption and mitochondrial activity but decreased lactic acid production. They also exhibited higher levels of argininosuccinate synthetase (ASS) and fumarasemRNA,which contributed tooxidativemetabolism (OXMET)when comparedwithparental cells. Restoring intracellular TRX1 protein in cisplatin-resistant cells resulted in lowering ASS and fumarase mRNAs, which in turn sensitized them to arginine deprivation. Interestingly, cisplatin-resistant cells also had significantly higher basal levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Overexpressing TRX1 lowered ACC and FAS proteins expressions in cisplatin-resistant cells. Chemical inhibition and short interfering RNA of ACC resulted in significant cell death in cisplatin-resistant compared with parental cells. Conversely,TRX1overexpressed cisplatin-resistant cells resisted5-(tetradecyloxy)-2-furoicacid (TOFA)-induced death.Collectively, loweringTRX1expression through increased secretion leads cisplatin-resistant cells to higher ROS production and increased dependency on OXMET. These changes raise an intriguing therapeutic potential for future therapy in cisplatin-resistant lung cancer. Mol Cancer Ther; 11(3); 604–15. 2012 AACR.