Thioredoxin 1 upregulates FOXO1 transcriptional activity in drug resistance in ovarian cancer cells

• Trx1 and FOXO1 are involved in drug resistance in ovarian cancer cells.
• Taxol-induced ROS regulate Trx1 and FOXO1 nuclear translocation in A2780 cells.
• Trx1 binds to FOXO1 and upregulates FOXO1 transcriptional activity.
• The regulation of FOXO1 by Trx1 might depend on Trx1 nuclear translocation.
• Trx1/FOXO1 signaling might be involved in drug resistance in ovarian cancer cells.

Drug resistance is the major cause of failure of cancer chemotherapy in ovarian cancer. However, the molecular mechanisms on the regulation of drug resistance are not fully understood. Here we showed that Trx1 and FOXO1 were involved in paclitaxel (PTX)-induced drug resistance in ovarian cancer A2780 cells. PTX induced reactive oxygen species (ROS) and resulted in Trx1 and FOXO1 nuclear translocation. We further found that Trx1 bound to FOXO1 and enhanced FOXO1 transcriptional activity; however Trx1 C69S mutant which is barely detected in the nucleus downregulated Trx1–FOXO1 interaction and Trx1-induced FOXO1 transcriptional activation. Silencing of FOXO1 abrogated Trx1-induced drug resistance. Trx1 increased FOXO1-induced drug resistance, while Trx1 C69S mutant completely abolished the regulation of FOXO1-mediated drug resistance by Trx1. These findings provided a novel mechanism on Trx1/FOXO1 signaling in drug resistance in ovarian cancer cells.