SGK2 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating GPX4

Abstract

Recent research has shown that ferroptosis, the iron-dependent accumulation of lipid peroxides that leads to cell death, suppresses cancer metastasis. However, the role of ferroptosis in prostate cancer metastasis has not been completely elucidated. In the current study, we identified the essential role of serum/glucocorticoid regulated kinase 2 (SGK2) in promoting prostate cancer metastasis by inhibiting ferroptosis. We found that the expression of SGK2 was higher in metastatic prostate cancer and predicted poor clinical outcomes. SGK2 knockdown inhibited the metastatic capacity of prostate cancer cells in vivo and in vitro, while SGK2 overexpression inhibited ferroptosis and facilitated prostate cancer metastasis by phosphorylating the Thr-24 and Ser-319 sites of forkhead box O1 (FOXO1). This process induced the translocation of FOXO1 from the nucleus to the cytoplasm, relieving the inhibitory effect of FOXO1 on glutathione peroxidase 4 (GPX4). These findings delineated a novel role of SGK2 in ferroptosis regulation of prostate cancer metastasis, identifying a new key pathway driving prostate cancer metastasis and potentially providing new treatment strategies for metastatic prostate cancer.

Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4

“…1 A) [ [8] , [9] , [10] ]. Many cancer types show an upregulation of GPXs to compensate for increased hydroperoxide levels, or as a function of altered signaling, and these important enzymes have been described as modulators of metastases [ 7 , [11] , [12] , [13] ]. The three primary isoforms, GPX1, GPX2, and GPX4, differ in expression and substrate specificity.…”

Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival inAR-altered lethal prostate cancer

“…Corroborating expected biology, these included genes known to play major roles in the processes associated with stemness, cellular proliferation, and selfrenewal. [15][16][17][18][19] Further, suggesting a connection with AR/enhancer altered lethal mCRPC, the ten genes most associated with stemness were promoter hypo-methylated in this more lethal disease state, while the ten genes least associated with stemness were promoter hyper-methylated (Figure 4D and 4E).…”

The molecular landscape of cellular metal ion biology

“…Metal ions are integral to the functioning of biological systems with critical roles in biochemical reactions 1 , vital metabolic pathways 2 , protein evolution 3 , and diseases like neurodegeneration 4 , cancer 5 and microbial infections 6 . As catalysts in enzyme active sites, reactant co-factors in redox reactions and by mediating protein-protein and protein-small molecule interactions, metal ions are required for energy transformation, biosynthesis, stress response and cellular signalling within prokaryotic, archaean and eukaryotic metabolic networks 7 .…”