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Open AccessArticle

Blockage of Glyoxalase I Inhibits Colorectal Tumorigenesis and Tumor Growth via Upregulation of STAT1, p53, and Bax and Downregulation of c-Myc and Bcl-2

by Yuan Chen, Lei Fang, Jiali Zhang, Gefei Li, Mengni Ma, Changxi Li, Jianxin Lyu and Qing H. Meng

Int. J. Mol. Sci. 2017, 18(3), 570; https://doi.org/10.3390/ijms18030570 - 9 Mar 2017

Cited by 21 | Viewed by 6437

Abstract

GlyoxalaseI (GLOI) is an enzyme that catalyzes methylglyoxal metabolism. Overexpression of GLOI has been documented in numerous tumor tissues, including colorectal cancer (CRC). The antitumor effects of GLOI depletion have been demonstrated in some types of cancer, but its role in CRC and [...] Read more.

GlyoxalaseI (GLOI) is an enzyme that catalyzes methylglyoxal metabolism. Overexpression of GLOI has been documented in numerous tumor tissues, including colorectal cancer (CRC). The antitumor effects of GLOI depletion have been demonstrated in some types of cancer, but its role in CRC and the mechanisms underlying this activity remain largely unknown. Our purpose was to investigate the antitumor effects of depleted GLOI on CRC in vitro and in vivo. RNA interference was used to deplete GLOI activity in four CRC cell lines. The cells’ proliferation, apoptosis, migration, and invasion were assessed by using the Cell Counting Kit-8, plate colony formation assay, flow cytometry, and transwell assays. Protein and mRNA levels were analyzed by western blot and quantitative real-time PCR (qRT-PCR), respectively. The antitumor effect of GLOI depletion in vivo was investigated in a SW620 xenograft tumor model in BALB/c nude mice. Our results show that GLOI is over-expressed in the CRC cell lines. GLOI depletion inhibited the proliferation, colony formation, migration, and invasion and induced apoptosis of all CRC cells compared with the controls. The levels of signal transducer and activator of transcription 1 (STAT1), p53, and Bcl-2 assaciated X protein (Bax) were upregulated by GLOI depletion, while cellular homologue of avian myelocytomatosis virus oncogene (c-Myc) and B cell lymphoma/lewkmia-2 (Bcl-2) were downregulated. Moreover, the growth of SW620-induced CRC tumors in BALB/c nude mice was significantly attenuated by GLOI depletion. The expression levels of STAT1, p53, and Bax were increased and those of c-Myc and Bcl-2 were decreased in the GLOI-depleted tumors. Our findings demonstrate that GLOI depletion has an antitumor effect through the STAT1 or p53 signaling pathways in CRC, suggesting that GLOI is a potential therapeutic target. Full article

(This article belongs to the Special Issue Glyoxalase System)

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1743 KiB

Open AccessArticle

Intracellular Accumulation of Methylglyoxal by Glyoxalase 1 Knock Down Alters Collagen Homoeostasis in L6 Myoblasts

by Bernd Stratmann, Bernhard Goldstein, Paul J. Thornalley, Naila Rabbani and Diethelm Tschoepe

Int. J. Mol. Sci. 2017, 18(3), 480; https://doi.org/10.3390/ijms18030480 - 23 Feb 2017

Cited by 25 | Viewed by 6446

Abstract

Hyperglycemia results in accumulation of the reactive dicarbonyl methylglyoxal (MG). Methylglyoxal is detoxified by the glyoxalase system (glyoxalase 1 and 2). The influence of glyoxalase 1 knockdown on expression of collagens 1, 3, 4, and 5 in L6 myoblasts under hyperglycemic conditions was [...] Read more.

Hyperglycemia results in accumulation of the reactive dicarbonyl methylglyoxal (MG). Methylglyoxal is detoxified by the glyoxalase system (glyoxalase 1 and 2). The influence of glyoxalase 1 knockdown on expression of collagens 1, 3, 4, and 5 in L6 myoblasts under hyperglycemic conditions was investigated. Increased biosynthesis of collagens 1, 3, 4, and 5 was detected at mRNA-level following knockdown of glyoxalase 1 (GLO1). At the protein level a significant elevation of the concentration of collagen 1 and 4 was shown, whereas no increase of collagen 5 and a non-significant increase in collagen 3 were detectable. These results could partially explain MG-induced changes in the extracellular matrix (ECM) which account for increased fibrosis and impaired function in myocytes. The mechanisms by which reactive glucose metabolites influence ECM composition deserve further investigation. Full article

(This article belongs to the Special Issue Glyoxalase System)

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8658 KiB

Open AccessArticle

Methylglyoxal-Mediated Stress Correlates with High Metabolic Activity and Promotes Tumor Growth in Colorectal Cancer

by Barbara Chiavarina, Marie-Julie Nokin, Justine Bellier, Florence Durieux, Noëlla Bletard, Félicie Sherer, Pierre Lovinfosse, Olivier Peulen, Laurine Verset, Romain Dehon, Pieter Demetter, Andrei Turtoi, Koji Uchida, Serge Goldman, Roland Hustinx, Philippe Delvenne, Vincent Castronovo and Akeila Bellahcène

Int. J. Mol. Sci. 2017, 18(1), 213; https://doi.org/10.3390/ijms18010213 - 21 Jan 2017

Cited by 51 | Viewed by 8552

Abstract

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several [...] Read more.

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several pathologies including cancer. All mammalian cells have an enzymatic defense against MG composed by glyoxalases GLO1 and GLO2 that converts MG to d-lactate. Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality. In this study, we used immunohistochemistry to examine the level of MG protein adducts, in a series of 102 CRC human tumors divided into four clinical stages. We consistently detected a high level of MG adducts and low GLO1 activity in high stage tumors compared to low stage ones suggesting a pro-tumor role for dicarbonyl stress. Accordingly, GLO1 depletion in CRC cells promoted tumor growth in vivo that was efficiently reversed using carnosine, a potent MG scavenger. Our study represents the first demonstration that MG adducts accumulation is a consistent feature of high stage CRC tumors. Our data point to MG production and detoxification levels as an important molecular link between exacerbated glycolytic activity and CRC progression. Full article

(This article belongs to the Special Issue Glyoxalase System)

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2256 KiB

Open AccessArticle

Modulation of GLO1 Expression Affects Malignant Properties of Cells

by Antje Hutschenreuther, Marina Bigl, Nasr Y. A. Hemdan, Tewodros Debebe, Frank Gaunitz and Gerd Birkenmeier

Int. J. Mol. Sci. 2016, 17(12), 2133; https://doi.org/10.3390/ijms17122133 - 18 Dec 2016

Cited by 26 | Viewed by 5041

Abstract

The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs [...] Read more.

The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1) that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system. Here, we overexpressed GLO1 in HEK 293 cells and silenced it in MCF-7 cells using shRNA. Tumor-related properties of wild type and transformed cells were compared and key glycolytic enzyme activities assessed. Furthermore, the cells were subjected to hypoxic conditions to analyze the impact on cell proliferation and enzyme activities. Our results demonstrate that knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas no functional alterations where found by overexpression of GLO1 in HEK 293 cells. In contrast, hypoxia caused inhibition of cell growth of all cells except of those overexpressing GLO1. Altogether, we conclude that GLO1 on one hand is crucial to maintaining tumor characteristics of malignant cells, and, on the other hand, supports malignant transformation of cells in a hypoxic environment when overexpressed. Full article

(This article belongs to the Special Issue Glyoxalase System)

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Review

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6435 KiB

Open AccessReview

Glyoxalase Goes Green: The Expanding Roles of Glyoxalase in Plants

by Subramanian Sankaranarayanan, Muhammad Jamshed, Abhinandan Kumar, Logan Skori, Sabine Scandola, Tina Wang, David Spiegel and Marcus A. Samuel

Int. J. Mol. Sci. 2017, 18(4), 898; https://doi.org/10.3390/ijms18040898 - 24 Apr 2017

Cited by 69 | Viewed by 8260

Abstract

The ubiquitous glyoxalase enzymatic pathway is involved in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis. The glyoxalase system has been more extensively studied in animals versus plants. Plant glyoxalases have been primarily associated with stress responses and their overexpression is [...] Read more.

The ubiquitous glyoxalase enzymatic pathway is involved in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis. The glyoxalase system has been more extensively studied in animals versus plants. Plant glyoxalases have been primarily associated with stress responses and their overexpression is known to impart tolerance to various abiotic stresses. In plants, glyoxalases exist as multigene families, and new roles for glyoxalases in various developmental and signaling pathways have started to emerge. Glyoxalase-based MG detoxification has now been shown to be important for pollination responses. During self-incompatibility response in Brassicaceae, MG is required to target compatibility factors for proteasomal degradation, while accumulation of glyoxalase leads to MG detoxification and efficient pollination. In this review, we discuss the importance of glyoxalase systems and their emerging biological roles in plants. Full article

(This article belongs to the Special Issue Glyoxalase System)

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1123 KiB

Open AccessReview

Characteristic Variations and Similarities in Biochemical, Molecular, and Functional Properties of Glyoxalases across Prokaryotes and Eukaryotes

by Charanpreet Kaur, Shweta Sharma, Mohammad Rokebul Hasan, Ashwani Pareek, Sneh L. Singla-Pareek and Sudhir K. Sopory

Int. J. Mol. Sci. 2017, 18(4), 250; https://doi.org/10.3390/ijms18040250 - 30 Mar 2017

Cited by 25 | Viewed by 6407

Abstract

The glyoxalase system is the ubiquitous pathway for the detoxification of methylglyoxal (MG) in the biological systems. It comprises two enzymes, glyoxalase I (GLYI) and glyoxalase II (GLYII), which act sequentially to convert MG into d-lactate, thereby helping living systems get rid [...] Read more.

The glyoxalase system is the ubiquitous pathway for the detoxification of methylglyoxal (MG) in the biological systems. It comprises two enzymes, glyoxalase I (GLYI) and glyoxalase II (GLYII), which act sequentially to convert MG into d-lactate, thereby helping living systems get rid of this otherwise cytotoxic byproduct of metabolism. In addition, a glutathione-independent GLYIII enzyme activity also exists in the biological systems that can directly convert MG to d-lactate. Humans and Escherichia coli possess a single copy of GLYI (encoding either the Ni- or Zn-dependent form) and GLYII genes, which through MG detoxification provide protection against various pathological and disease conditions. By contrast, the plant genome possesses multiple GLYI and GLYII genes with a role in abiotic stress tolerance. Plants possess both Ni²⁺- and Zn²⁺-dependent forms of GLYI, and studies on plant glyoxalases reveal the various unique features of these enzymes distinguishing them from prokaryotic and other eukaryotic glyoxalases. Through this review, we provide an overview of the plant glyoxalase family along with a comparative analysis of glyoxalases across various species, highlighting similarities as well as differences in the biochemical, molecular, and physiological properties of these enzymes. We believe that the evolution of multiple glyoxalases isoforms in plants is an important component of their robust defense strategies. Full article

(This article belongs to the Special Issue Glyoxalase System)

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831 KiB

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Methylglyoxal-Derived Advanced Glycation Endproducts in Multiple Sclerosis

by Suzan Wetzels, Kristiaan Wouters, Casper G. Schalkwijk, Tim Vanmierlo and Jerome J. A. Hendriks

Int. J. Mol. Sci. 2017, 18(2), 421; https://doi.org/10.3390/ijms18020421 - 15 Feb 2017

Cited by 59 | Viewed by 9550

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The activation of inflammatory cells is crucial for the development of MS and is shown to induce intracellular glycolytic metabolism in pro-inflammatory microglia and macrophages, as well as CNS-resident astrocytes. [...] Read more.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The activation of inflammatory cells is crucial for the development of MS and is shown to induce intracellular glycolytic metabolism in pro-inflammatory microglia and macrophages, as well as CNS-resident astrocytes. Advanced glycation endproducts (AGEs) are stable endproducts formed by a reaction of the dicarbonyl compounds methylglyoxal (MGO) and glyoxal (GO) with amino acids in proteins, during glycolysis. This suggests that, in MS, MGO-derived AGEs are formed in glycolysis-driven cells. MGO and MGO-derived AGEs can further activate inflammatory cells by binding to the receptor for advanced glycation endproducts (RAGE). Recent studies have revealed that AGEs are increased in the plasma and brain of MS patients. Therefore, AGEs might contribute to the inflammatory status in MS. Moreover, the main detoxification system of dicarbonyl compounds, the glyoxalase system, seems to be affected in MS patients, which may contribute to high MGO-derived AGE levels. Altogether, evidence is emerging for a contributing role of AGEs in the pathology of MS. In this review, we provide an overview of the current knowledge on the involvement of AGEs in MS. Full article

(This article belongs to the Special Issue Glyoxalase System)

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1699 KiB

Open AccessReview

Coordinated Actions of Glyoxalase and Antioxidant Defense Systems in Conferring Abiotic Stress Tolerance in Plants

by Mirza Hasanuzzaman, Kamrun Nahar, Md. Shahadat Hossain, Jubayer Al Mahmud, Anisur Rahman, Masashi Inafuku, Hirosuke Oku and Masayuki Fujita

Int. J. Mol. Sci. 2017, 18(1), 200; https://doi.org/10.3390/ijms18010200 - 20 Jan 2017

Cited by 208 | Viewed by 13014

Abstract

Being sessile organisms, plants are frequently exposed to various environmental stresses that cause several physiological disorders and even death. Oxidative stress is one of the common consequences of abiotic stress in plants, which is caused by excess generation of reactive oxygen species (ROS). [...] Read more.

Being sessile organisms, plants are frequently exposed to various environmental stresses that cause several physiological disorders and even death. Oxidative stress is one of the common consequences of abiotic stress in plants, which is caused by excess generation of reactive oxygen species (ROS). Sometimes ROS production exceeds the capacity of antioxidant defense systems, which leads to oxidative stress. In line with ROS, plants also produce a high amount of methylglyoxal (MG), which is an α-oxoaldehyde compound, highly reactive, cytotoxic, and produced via different enzymatic and non-enzymatic reactions. This MG can impair cells or cell components and can even destroy DNA or cause mutation. Under stress conditions, MG concentration in plants can be increased 2- to 6-fold compared with normal conditions depending on the plant species. However, plants have a system developed to detoxify this MG consisting of two major enzymes: glyoxalase I (Gly I) and glyoxalase II (Gly II), and hence known as the glyoxalase system. Recently, a novel glyoxalase enzyme, named glyoxalase III (Gly III), has been detected in plants, providing a shorter pathway for MG detoxification, which is also a signpost in the research of abiotic stress tolerance. Glutathione (GSH) acts as a co-factor for this system. Therefore, this system not only detoxifies MG but also plays a role in maintaining GSH homeostasis and subsequent ROS detoxification. Upregulation of both Gly I and Gly II as well as their overexpression in plant species showed enhanced tolerance to various abiotic stresses including salinity, drought, metal toxicity, and extreme temperature. In the past few decades, a considerable amount of reports have indicated that both antioxidant defense and glyoxalase systems have strong interactions in conferring abiotic stress tolerance in plants through the detoxification of ROS and MG. In this review, we will focus on the mechanisms of these interactions and the coordinated action of these systems towards stress tolerance. Full article

(This article belongs to the Special Issue Glyoxalase System)

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1031 KiB

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Methylglyoxal-Glyoxalase 1 Balance: The Root of Vascular Damage

by Cecilia Nigro, Alessia Leone, Gregory Alexander Raciti, Michele Longo, Paola Mirra, Pietro Formisano, Francesco Beguinot and Claudia Miele

Int. J. Mol. Sci. 2017, 18(1), 188; https://doi.org/10.3390/ijms18010188 - 18 Jan 2017

Cited by 91 | Viewed by 9040

Abstract

The highly reactive dicarbonyl methylglyoxal (MGO) is mainly formed as byproduct of glycolysis. Therefore, high blood glucose levels determine increased MGO accumulation. Nonetheless, MGO levels are also increased as consequence of the ineffective action of its main detoxification pathway, the glyoxalase system, of [...] Read more.

The highly reactive dicarbonyl methylglyoxal (MGO) is mainly formed as byproduct of glycolysis. Therefore, high blood glucose levels determine increased MGO accumulation. Nonetheless, MGO levels are also increased as consequence of the ineffective action of its main detoxification pathway, the glyoxalase system, of which glyoxalase 1 (Glo1) is the rate-limiting enzyme. Indeed, a physiological decrease of Glo1 transcription and activity occurs not only in chronic hyperglycaemia but also with ageing, during which MGO accumulation occurs. MGO and its advanced glycated end products (AGEs) are associated with age-related diseases including diabetes, vascular dysfunction and neurodegeneration. Endothelial dysfunction is the first step in the initiation, progression and clinical outcome of vascular complications, such as retinopathy, nephropathy, impaired wound healing and macroangiopathy. Because of these considerations, studies have been centered on understanding the molecular basis of endothelial dysfunction in diabetes, unveiling a central role of MGO-Glo1 imbalance in the onset of vascular complications. This review focuses on the current understanding of MGO accumulation and Glo1 activity in diabetes, and their contribution on the impairment of endothelial function leading to diabetes-associated vascular damage. Full article

(This article belongs to the Special Issue Glyoxalase System)

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Glycative Stress and Its Defense Machinery Glyoxalase 1 in Renal Pathogenesis

by Yosuke Hirakawa and Reiko Inagi

Int. J. Mol. Sci. 2017, 18(1), 174; https://doi.org/10.3390/ijms18010174 - 17 Jan 2017

Cited by 14 | Viewed by 6300

Abstract

Chronic kidney disease is a major public health problem around the world. Because the kidney plays a role in reducing glycative stress, renal dysfunction results in increased glycative stress. In turn, glycative stress, especially that due to advanced glycated end products (AGEs) and [...] Read more.

Chronic kidney disease is a major public health problem around the world. Because the kidney plays a role in reducing glycative stress, renal dysfunction results in increased glycative stress. In turn, glycative stress, especially that due to advanced glycated end products (AGEs) and their precursors such as reactive carbonyl compounds, exacerbates chronic kidney disease and is related to premature aging in chronic kidney disease, whether caused by diabetes mellitus or otherwise. Factors which hinder a sufficient reduction in glycative stress include the inhibition of anti-glycation enzymes (e.g., GLO-1), as well as pathogenically activated endoplasmic reticulum (ER) stress and hypoxia in the kidney. Promising strategies aimed at halting the vicious cycle between chronic kidney disease and increases in glycative stress include the suppression of AGE accumulation in the body and the enhancement of GLO-1 to strengthen the host defense machinery against glycative stress. Full article

(This article belongs to the Special Issue Glyoxalase System)

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2205 KiB

Open AccessReview

Bacterial Responses to Glyoxal and Methylglyoxal: Reactive Electrophilic Species

by Changhan Lee and Chankyu Park

Int. J. Mol. Sci. 2017, 18(1), 169; https://doi.org/10.3390/ijms18010169 - 17 Jan 2017

Cited by 63 | Viewed by 11432

Abstract

Glyoxal (GO) and methylglyoxal (MG), belonging to α-oxoaldehydes, are produced by organisms from bacteria to humans by glucose oxidation, lipid peroxidation, and DNA oxidation. Since glyoxals contain two adjacent reactive carbonyl groups, they are referred to as reactive electrophilic species (RES), and are [...] Read more.

Glyoxal (GO) and methylglyoxal (MG), belonging to α-oxoaldehydes, are produced by organisms from bacteria to humans by glucose oxidation, lipid peroxidation, and DNA oxidation. Since glyoxals contain two adjacent reactive carbonyl groups, they are referred to as reactive electrophilic species (RES), and are damaging to proteins and nucleotides. Therefore, glyoxals cause various diseases in humans, such as diabetes and neurodegenerative diseases, from which all living organisms need to be protected. Although the glyoxalase system has been known for some time, details on how glyoxals are sensed and detoxified in the cell have not been fully elucidated, and are only beginning to be uncovered. In this review, we will summarize the current knowledge on bacterial responses to glyoxal, and specifically focus on the glyoxal-associated regulators YqhC and NemR, as well as their detoxification mediated by glutathione (GSH)-dependent/independent glyoxalases and NAD(P)H-dependent reductases. Furthermore, we will address questions and future directions. Full article

(This article belongs to the Special Issue Glyoxalase System)

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Open AccessHypothesis

Increased Dicarbonyl Stress as a Novel Mechanism of Multi-Organ Failure in Critical Illness

by Bas C. T. Van Bussel, Marcel C. G. Van de Poll, Casper G. Schalkwijk and Dennis C. J. J. Bergmans

Int. J. Mol. Sci. 2017, 18(2), 346; https://doi.org/10.3390/ijms18020346 - 7 Feb 2017

Cited by 9 | Viewed by 4701

Abstract

Molecular pathological pathways leading to multi-organ failure in critical illness are progressively being unravelled. However, attempts to modulate these pathways have not yet improved the clinical outcome. Therefore, new targetable mechanisms should be investigated. We hypothesize that increased dicarbonyl stress is such a [...] Read more.

Molecular pathological pathways leading to multi-organ failure in critical illness are progressively being unravelled. However, attempts to modulate these pathways have not yet improved the clinical outcome. Therefore, new targetable mechanisms should be investigated. We hypothesize that increased dicarbonyl stress is such a mechanism. Dicarbonyl stress is the accumulation of dicarbonyl metabolites (i.e., methylglyoxal, glyoxal, and 3-deoxyglucosone) that damages intracellular proteins, modifies extracellular matrix proteins, and alters plasma proteins. Increased dicarbonyl stress has been shown to impair the renal, cardiovascular, and central nervous system function, and possibly also the hepatic and respiratory function. In addition to hyperglycaemia, hypoxia and inflammation can cause increased dicarbonyl stress, and these conditions are prevalent in critical illness. Hypoxia and inflammation have been shown to drive the rapid intracellular accumulation of reactive dicarbonyls, i.e., through reduced glyoxalase-1 activity, which is the key enzyme in the dicarbonyl detoxification enzyme system. In critical illness, hypoxia and inflammation, with or without hyperglycaemia, could thus increase dicarbonyl stress in a way that might contribute to multi-organ failure. Thus, we hypothesize that increased dicarbonyl stress in critical illness, such as sepsis and major trauma, contributes to the development of multi-organ failure. This mechanism has the potential for new therapeutic intervention in critical care. Full article

(This article belongs to the Special Issue Glyoxalase System)

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