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Area of Science:

  • Biochemistry and Molecular Biology
  • Cancer Research
  • Metabolic Health Disparities

Background:

  • Prostate cancer (PCa) disproportionately affects African American/Black (AA/B) men, with obesity linked to increased mortality.
  • Obesity elevates methylglyoxal (MG), a reactive metabolite implicated in metabolic dysregulation and cancer progression.
  • MG forms adducts on DNA, RNA, and proteins, potentially disrupting cellular functions.

Purpose of the Study:

  • To investigate the role of methylglyoxal (MG) and its detoxification enzyme, glyoxalase 1 (GLO1), in prostate cancer (PCa) disparities.
  • To explore the association between MG adducts, GLO1 genetic variants, and metabolic alterations in PCa between ethnic groups.

Main Methods:

  • Quantified MG adducts in PCa patients of different ethnicities (AA/B vs. European American/EA).
  • Genotyped the GLO1 SNP rs1049346 in PCa patients and analyzed GLO1 expression and activity in EA (C4-2) and AA/B (MDA-PCa-2b) PCa cell lines.
  • Assessed MG's impact on DNA repair, RNA processing, and cellular metabolism (glycolysis, oxidative phosphorylation) using transcriptomic and metabolic analyses.

Main Results:

  • MG adducts were elevated in AA/B men with PCa compared to EA men with PCa and non-PCa individuals.
  • AA/B men with PCa showed higher frequency of the GLO1 variant rs1049346, associated with reduced GLO1 activity and increased MG adducts in MDA-PCa-2b cells.
  • MG exposure induced distinct metabolic reprogramming and stress responses, including increased glycolysis and TXNIP induction, particularly in the AA/B cell line.

Conclusions:

  • Elevated MG stress and impaired GLO1 detoxification may contribute to PCa progression and ethnic disparities in AA/B men.
  • MG-induced metabolic reprogramming and altered stress responses highlight potential therapeutic targets for precision medicine in PCa.