Glyoxalase 2 drives tumorigenesis in human prostate cells in a mechanism involving androgen receptor and p53‐p21 axis

Abstract

Glyoxalase 2 (Glo2), a metabolic enzyme, is overexpressed in some human cancers which suggests this enzyme may play a role in human tumorigenesis. In prostate cancer (PCa), the role of Glo2 has been scarcely investigated and there are no studies addressing a causative involvement of this protein in this neoplasia. Here, we examined the immunohistochemical profile of Glo2 in human PCa and benign adjacent tissues and investigated Glo2 involvement in PCa development in human prostate cell lines. PCa and matched adjacent normal tissues were obtained from paraffin sections of primary PCa from 20 patients who had undergone radical prostatectomy. Histopathological diagnosis was confirmed for each sample. Glo2 expression analysis was performed by immunohistochemistry in prostate tissues, and by qRT-PCR and immunoblotting in prostate cell lines. The causative and mechanistic role of Glo2 in prostate tumorigenesis was demonstrated by Glo2 ectopic expression/silencing and employing specific activators/inhibitors. Our results showed that Glo2 was selectively expressed in PCa but not in the luminal compartment of the adjacent benign epithelium consistently in all the examined 20 cases. Glo2 expression in PCa was dependent on androgen receptor (AR) and was aimed at stimulating cell proliferation and eluding apoptosis through a mechanism involving the p53-p21 axis. Glo2 was intensely expressed in the basal cells of benign glands but was not involved in PCa genesis. Our results demonstrate for the first time that Glo2 drives prostate tumorigenesis and suggest that it may represent a novel adjuvant marker in the pathological diagnosis of early PCa.

Glyoxalases in Urological Malignancies

“…Methylglyoxal is metabolized mainly by glyoxalases [ 71 , 72 , 73 , 74 , 75 , 76 , 77 ], with minor metabolism by aldoketo reductases (AKRs) and aldehyde dehydrogenases (ADHs) [ 19 , 40 , 78 , 79 , 80 , 81 ] that convert it to hydroxyacetone and pyruvate, respectively [ 82 ]. Glyoxalases are cellular enzymes whose increased expression and activity in tumor tissues and/or cell lines [ 77 , 83 , 84 , 85 ], including those from the urogenital tract [ 86 , 87 , 88 , 89 , 90 ], have been widely documented [ 77 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]. In the present review, we provide an overview of the role of glyoxalases in the onset and progression of human urogenital malignancies and glyoxalases’ potential as targets for anticancer drug development and biomarkers for diagnosis or prognosis of urological cancers.…”

Glyoxalases in Urological Malignancies

“…However, the scanty number of PCa samples considered in those studies significantly limited a reliable interpretation on the biological significance of Glo2 in this neoplasia. Only recently we causatively demonstrated a role of Glo2 in this neoplasia [36,37] providing in vivo and, in vitro, evidence for a role of this enzyme in prostate carcinogenesis. In particular, we showed that Glo2 was selectively expressed in PCa but not in the luminal compartment of the adjacent benign epithelium consistently in all the examined cases (n = 20).…”

“…Notably, a distinctly high activity of Glo1 was observed in 22 out of 22 PCa specimens and none to little activity in 10 out of 10 non-malignant specimens. Although preliminary, these results opened new pathways of investigation towards the study of Glo1 expression, either at mRNA, protein or functional level, in PCa tissues and normal counterparts or in differently aggressive and invasive PCas [36,37,[52][53][54][55]. Overall, these studies strongly indicated Glo1 as a novel important protein involved in PCa genesis and progression, thus suggesting an oncogenic role for this enzyme in this neoplasm.…”

“…Differently from Glo1, the role of Glo2 in PCa has been scarcely investigated [36,37,49,50]. Ayoub et al [49] and Di Ilio et al [50] first attempted to evaluate Glo2 enzymatic activity in human PCa cell lines and tissues.…”

“…To further exacerbate the situation, at least some malignancies of the urinary tract are age-related, therefore, it is very plausible Glo1 activity can be regulated through several mechanisms including gene expression regulation [21,26,35,36] and post-translational modifications such as phosphorylation, NO-mediated modification and glutathionylation [21,[38][39][40][41]. Glo2 expression can be upregulated by the transcription factors p63 and p73 [42], steroid hormones [35], androgen receptor [37] and PTEN/PI3K/AKT/mTOR signalings [36]. Extensive information about physical and chemical properties of glyoxalases has been largely described in excellent previous reviews [43][44][45][46][47][48].…”