Selenoprotein Sepp1 regulates Cysteine Dependence in Pancreatic Cancer

Abstract Metabolic deregulations frequently occur in various cancers and differentiate cancer cells from normal cells. Such changes predispose cancer cells to potential vulnerabilities. There is rising interest in developing novel therapies to target tumor metabolic vulnerability. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of cancer in pancreas and ranks as the second most lethal cancer in USA due to lack of effective targeted therapy options. Targeting cysteine dependence of cancer cells by blocking cysteine uptake or inhibition of glutathione peroxidase 4 (GPX4) can eliminate many types of cancer cells via ferroptotic cell death. We observed that PDACs show differential vulnerability to cysteine depletion, which associates with the epithelial-mesenchymal transition (EMT) status of tumor cells. Two subtypes of PDAC are derived from these phenotypic disparities: The mesenchymal-type tumor cells are significantly sensitive to targeted cysteine therapy, while the epithelial-type responds reluctantly. We found that the selenoprotein Sepp1 expression is greatly reduced in mesenchymal tumor cells, and its suppression sensitizes epithelial-type tumor cells to ferroptosis inducers. Sepp1 is a major reservoir and transporter of selenium in plasma and functions as a tissue and cell antioxidant. In line with this, addition of selenium alleviates cell reliance on cysteine and protects mesenchymal-type tumor cells from ferroptosis inducers. We further revealed that loss of Sepp1 compromises activity of the thioredoxin system by gene regulation on both transcriptional and translational levels. Overall, our findings suggested that Sepp1 regulates cysteine-dependence by modulating the thioredoxin system. Also, the inhibition of thioredoxin reductases can synergize with targeted cysteine therapy to overcome drug resistance in epithelial-subtype pancreatic cancer.