Glyoxalases in Urological Malignancies

Abstract

Urological cancers include a spectrum of malignancies affecting organs of the reproductive and/or urinary systems, such as prostate, kidney, bladder, and testis. Despite improved primary prevention, detection and treatment, urological cancers are still characterized by an increasing incidence and mortality worldwide and although advances have been made toward understanding the molecular basis of these diseases, a complete insight of the pathogenic mechanisms is still a research challenge for defining safer pharmacological therapies and prognostic factors, especially for the metastatic stage of these neoplasms for which no effective therapies exist. Glyoxalases are enzymes that catalyzes the glutathione-dependent metabolism of cytotoxic methylglyoxal (MG), thus protecting against cellular damage and apoptosis. They are generally overexpressed in numerous cancers as a survival strategy by providing a safeguard through enhancement of MG detoxification. Increasing evidence suggest that glyoxalases, especially Glo1, would act as oncogenes in urological malignancies and be central to their initiation, growth and progression. In this review, we highlight the critical role of glyoxalases as regulators of tumorigenesis in the prostate through modulation of various critical signaling pathways, and provide an overview of the current knowledge on glyoxalases in bladder, kidney and testis cancers. We also discuss the promise and challenges for Glo1 inhibitors as future anti-PCa therapeutics and the potential of glyoxalases as biomarkers for PCa diagnosis.

Testosterone and Follicle Stimulating Hormone–Dependent Glyoxalase 1 Up-Regulation Sustains the Viability of Porcine Sertoli Cells through the Control of Hydroimidazolone– and Argpyrimidine-Mediated NF-κB Pathway

“…Glo1 is a frontline defense against dicarbonyl glycation in physiological systems, limiting carbonyl stress, a condition occurring under the overload of reactive carbonyl compounds, 15 especially MG, the substrate of Glo1. 14 AGEs derived from spontaneous MG adduction of arginine residues are, primarily, hydroimidazolone (MG-H1), 15,20 and, secondly, ArgPyr. 15 It has been described that both MG and MG-derived AGEs can trigger apoptosis in human cells.…”

“…14 AGEs derived from spontaneous MG adduction of arginine residues are, primarily, hydroimidazolone (MG-H1), 15,20 and, secondly, ArgPyr. 15 It has been described that both MG and MG-derived AGEs can trigger apoptosis in human cells. 26e31 In the present work, by performing Glo1 silencing and using the specific MG scavenger, AG, we demonstrated, for the first time to our knowledge, that Glo1 sustains viability of porcine prepubertal SCs costimulated with T and FSH, by limiting the intracellular accumulation of MG-H1 and ArgPyr that otherwise would induce a mitochondrial apoptotic pathway (Figure 8).…”

“…Thus, this study extends the limited understanding of the molecular control of Glo1 regulation. 15 The idea that SCs are essential for successful spermatogenesis has now gained wide acceptance. Indeed, the mechanism underpinning this effect is now also largely understood; SCs take up extracellular glucose and convert it into lactate, the preferred fuel of developing germ cells.…”

“…13 Glyoxalase 1 (Glo1) is the major detoxifying enzyme of methylglyoxal (MG), 14 a metabolic byproduct of glycolysis with a potent ability to modify primary amine-containing amino acid side chains (such as lysine and arginine residues) of key cellular proteins, generating advanced glycation end products (AGEs), whose intracellular accumulation leads to so-called carbonyl stress. 15 The modification of protein AGEs can affect their biological activity 16,17 or stability/ degradation, 18 leading to impaired cell function. 19 Hydroimidazolone (MG-H1) and argpyrimidine (ArgPyr) are two such AGEs derived from the spontaneous reaction of MG with protein arginine residues.…”

“…19 Hydroimidazolone (MG-H1) and argpyrimidine (ArgPyr) are two such AGEs derived from the spontaneous reaction of MG with protein arginine residues. 15,20,21 Several studies have demonstrated that MG-induced carbonyl stress can affect many biological processes in human cells, 22e24 including apoptosis. 25e32 By using the cofactor glutathione (GSH), Glo1 prevents the accumulation of MG, thereby suppressing dicarbonyl-mediated glycation reactions.…”