Glyoxalase 1-419C>A variant is associated with oxidative stress: implications in prostate cancer progression

Abstract

Glyoxalase 1 is a scavenging enzyme of potent precursors in reactive oxygen species formation and is involved in the occurrence and progression of human malignancies. Glyoxalase I A111E polymorphism has been suggested to influence its enzymatic activity. The present study was aimed at investigating the association of this polymorphism with oxidative stress and its implications in prostate cancer progression or survival. The polymorphism was genotyped in human differently aggressive and invasive prostate cancer cell lines, in 571 prostate cancer or 588 benign prostatic hyperplasia patients, and 580 healthy subjects by Polymerase Chain Reaction/Restriction Fragment Length Polymorphism. Glyoxalase 1 activity, the pro-oxidant Glyoxalase 1-related Argpyrimidine and oxidative stress biomarkers were evaluated by biochemical analyses. Glyoxalase 1 polymorphism was associated with an increase in Glyoxalase 1-related pro-oxidant Argpyrimidine and oxidative stress levels and cancer progression. The mutant A allele conferred a modest risk of prostate cancer, a marked risk of prostate cancer progression and a lower survival time, compared to the wild C allele. The results of our exploratory study point out a significant role for Glyoxalase 1 in prostate cancer progression, providing an additional candidate for risk assessment in prostate cancer patients and an independent prognostic factor for survival. Finally, we provided evidence of the biological plausibility of Glyoxalase 1 polymorphism, either alone or in combination with other ones, all related to oxidative stress control that represents a key event in PCa development and progression.

Figure 1. GLO1−419C>A polymorphism genotyping, argpyrimidine and oxidative stress indices in LNCaP and PC3 cells.

(A) GLO1 −419C>A homozygous wild type (CC) LNCaP and homozygous mutant type (AA) PC3 cells; (B) Argpyrimidine (AP) intracellular levels and densitometric analysis from Western blot detection. Western blot was obtained by using a mAb mouse anti-AP. The blot was stripped of the bound Ab and re-probed with mouse anti-β-actin, to confirm equal loading. The Western blot shown is representative of three separate experiments. (C) Reactive oxygen species (ROS), malondialdehyde (MDA) and reduced glutathione (GSH) intracellular levels. Histograms indicate means ± SD of three different cultures each of one was tested in quadruplicate and expressed as fold change.**P<0.001, **P<0.001.

Figure 2. Kaplan-Meier survival curves for localized or low grade prostate cancer patients subgroups by GLO1–419C>A.

The individuals with the variant CA/AA genotypes showed significantly lower survival rates than individuals with the CC genotype in both localized (A) or low grade (B) subgroups.