Abstract
Elimination of cisplatin-resistant lung cancer cells remains a major obstacle. We have shown that cisplatin-resistant tumors have higher reactive oxygen species (ROS) levels and can be 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 but decreased 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 fumarase mRNA, which contributed to oxidative metabolism (OXMET) when compared with parental 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, TRX1 overexpressed cisplatin-resistant cells resisted 5-(tetradecyloxy)-2-furoic acid (TOFA)-induced death. Collectively, lowering TRX1 expression 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.
Highlights
Cisplatin is a widely used therapeutic agent in the treatment of several types of solid tumors including lung cancer, head and neck and ovarian cancer
Since it has been reported that TRX1 can be secreted from cells through the leaderless secretory pathway [19], it is possible that lower TRX1 found in cisplatin resistant (CR) cells may be due to the excessive secretion of this protein
Taken together from the in vitro and in vivo models, our findings suggest that CR cells possess lower intracellular TRX1 protein that is not due to a transcriptional consequence, but rather due to an increase in secretion resulting in higher reactive oxygen species (ROS) accumulation
Summary
Cisplatin is a widely used therapeutic agent in the treatment of several types of solid tumors including lung cancer (both small cell and non small cell), head and neck and ovarian cancer. A number of investigators have shown that cisplatin can inhibit thioredoxin reductase (TrxR1), a thioredoxin reducing enzyme, which leads to increased ROS, resulting in further damage of DNA and subsequent cell death [3, 4]. We have reported lower thioredoxin (TRX1) in a panel of CR lung cancer cells tested [2]. It is not known whether decreased TRX1 protein was due to transcriptional down-regulation or increased in secretion. We investigated whether decreased TRX1 found in CR cells is regulated at the mRNA or the protein level and report our results
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