Mechanistic Link Between Glyoxalase 1 Expression and Methylglyoxal-Induced Oncogenic Stress in Prostate Cancer

Prostate cancer (PCa) is the second leading cause of cancer-related death in men, with African American/Black (AA/B) men experiencing significantly higher incidence and mortality than European American (EA) men. Obesity, which disproportionately affects AA/B men, is linked to increased PCa mortality, potentially through metabolic dysregulation. We hypothesize that methylglyoxal (MG), a reactive byproduct of glucose, lipid, and protein metabolism elevated in obesity, contributes to PCa progression. MG forms adducts on DNA, RNA, and proteins. Here, we found that MG-adducts are elevated in AA/B men with PCa compared to EA men and controls. AA/B men with PCa had a higher frequency of SNP rs1049346 in glyoxalase 1 (GLO1), the primary MG detoxification enzyme. PCa cell lines from EA (C4-2) and AA/B (MDA-PCa-2b) men showed differential SNP rs1049346 expression, with the former heterozygous and the latter homozygous for the SNP. This was associated with altered GLO1 expression and activity, with MDA-PCa-2b cells exhibiting reduced GLO1 function and increased MG-adducts compared to C4-2 cells. MG treatment altered DNA repair and RNA processing gene expression and induced distinct metabolic shifts in MDA-PCa-2b compared to C4-2 cells, including enhanced glycolysis and oxidative phosphorylation. Transcriptomic analysis revealed shared stress responses following MG treatment, but MDA-PCa-2b cells uniquely activated metallothionein and NOD1/2 immune signaling pathways in addition to TXNIP, a redox regulator linked to tumorigenicity in GLO1-deficient cancers. These findings suggest that MG stress may contribute to PCa progression in AA/B men through metabolic reprogramming and impaired detoxification, offering insight into racial disparities and potential therapeutic targets.