Role of glutathione disulfide reductase in colorectal cancer: a tumor suppressor

BACKGROUND: Glutathione-disulfide reductase (GSR) was responsible for maintaining the supply of reduced glutathione, and was found to be abnormally expressed in a variety of cancers. There was an incomplete understanding regarding the roles of GSR in colorectal cancer (CRC) today. METHODS: We used colorectal cancer tissues and cell lines to detect the function of GSR in CRC. We also used bioinformatics to analyze the related pathways of GSR in colorectal cancer. RESULTS: GSR mRNA was down-regulated in CRC (p < 0.05). The expression of GSR mRNA with T3 and T4 patients was lower than that with T1 and T2 patients, with M1 patients was lower than that with M0 patients, with N1 and N2 patients was lower than that with N0 stage patients, with stage 3 and stage 4 patients was lower than that with stage1 and stage 2 patients (p < 0.05). Overall survival (OS), disease-specific survival (DSS), progression survival (PFS), post-progression survival (PPS) and recurrence-free survival (RFS) time for patients with high expression of GSR was higher than that for patients with low GSR expression (p < 0.05). The expression of p-p38 MAPK and p-ERK increased in GSR knockdown cells, while the expression of p-Nrf2, KEAP1, p-PI3K and p-Akt decreased. Consistent with alterations in the MAPK/ERK signaling pathway, cells with GSR knockdown exhibited significantly enhanced proliferative, migratory, and invasive capabilities, along with increased ROS production (all p < 0.001), while showing a reduced apoptosis rate (p < 0.001). Furthermore, both re-expression of GSR and treatment with an ERK inhibitor effectively reversed the phenotypic and molecular changes induced by GSR knockdown. CONCLUSION: The expression of GSR was closely related to the development of colorectal cancer. GSR was low expressed and played a tumor-suppressive role through inhibiting the production of ROS, and the activation of p38 MAPK/ERK pathways in CRC. GSR has the potential to become a potential biomarker for the diagnosis and treatment of colorectal cancer.