Abstract 3032: Selenoprotein Sepp1 determines cysteine dependence in pancreatic cancer

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Department of Biological Sciences


Pancreatic cancer (PaCa) represents the fourth leading cause of overall cancer death, despite its relatively low incidence compared to other malignancies (Lung, prostate, breast, etc.). Approximately 57,600 people were estimated to be diagnosed with pancreatic cancer in the USA, and 47,050 were estimated to die of the disease in 2020 reported by The American Cancer Society. Novel effective therapeutic strategies are urgently needed. Metabolic changes are typically associated with tumor development to support fast cell proliferation and malignant transition. Such metabolic deregulations differentiate tumor cells from normal cells and act as potential targets of anticancer therapies. Previous studies have shown cysteine dependence often presents in various cancers, since cysteine metabolism supplies glutathione - an important substrate for the cellular reactive oxygen species (ROS) cleanup cycle. Studies in breast and kidney cancers have shown that such cysteine-dependence is a prominent feature in the cancer subtypes with a mesenchymal cell phenotype, instead of in the epithelial subtype. We found that cysteine dependence exists in pancreatic cancer as well. Mesenchymal PaCa cells, in contrast to the epithelial tumor cells, appear to be more sensitive to cysteine depletion with extensive induction of ferroptosis, a programmed cell death pathway involving iron and lipid peroxidation. Gene expression analysis revealed the selenium transporter protein Sepp1 to be absent in the mesenchymal PaCa cells. Knockdown of Sepp1 expression in cysteine-independent cells renders cells dependent on cysteine. Selenium is a micronutrient required for the synthesis of selenoproteins including GPX4 and Sepp1. The addition of selenium alleviated cell reliance on cysteine and caused resistance to GPX4 inhibitor-induced ferroptosis. We observed that Sepp1 regulates the thioredoxin pathway to rescue the cells under the glutathione deficiency. Interestingly, the conditioned media assay also revealed that Sepp1 protects cells from ROS stress by a symbiotic mechanism. Our findings suggest that Sepp1 could serve as a biomarker of tumor cysteine-dependency and a potential molecular target for therapeutic strategies to overcome drug resistance in pancreatic cancer.

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Cancer Research