Multiple roles of glyoxalase 1-mediated suppression of methylglyoxal glycation in cancer biology—Involvement in tumour suppression, tumour growth, multidrug resistance and target for chemotherapy

Abstract

Glyoxalase 1 (Glo1) is part of the glyoxalase system in the cytoplasm of all human cells. It catalyses the glutathione-dependent removal of the endogenous reactive dicarbonyl metabolite, methylglyoxal (MG). MG is formed mainly as a side product of anaerobic glycolysis. It modifies protein and DNA to form mainly hydroimidazolone MG-H1 and imidazopurinone MGdG adducts, respectively. Abnormal accumulation of MG, dicarbonyl stress, increases adduct levels which may induce apoptosis and replication catastrophe. In the non-malignant state, Glo1 is a tumour suppressor protein and small molecule inducers of Glo1 expression may find use in cancer prevention. Increased Glo1 expression is permissive for growth of tumours with high glycolytic activity and is thereby a biomarker of tumour growth. High Glo1 expression is a cause of multi-drug resistance. It is produced by over-activation of the Nrf2 pathway and GLO1 amplification. Glo1 inhibitors are antitumour agents, inducing apoptosis and necrosis, and anoikis. Tumour stem cells and tumours with high flux of MG formation and Glo1 expression are sensitive to Glo1 inhibitor therapy. It is likely that MG-induced cell death contributes to the mechanism of action of current antitumour agents. Common refractory tumours have high prevalence of Glo1 overexpression for which Glo1 inhibitors may improve therapy.

Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia

“…Up-regulation of MIF, DECR1, PAFAH1B2 and GLO1 (Fig. 2C) point to stress adaptation responses associated with chronic inflammation (32), altered metabolism (33), and signaling (34) as well as increased detoxification (35). Similar aging-related processes may as well account for the down-regulated proteins AMPD2, SLC6A4, PLSCR1 and TBXAS1 (Fig.…”

The metabolic repair enzyme phosphoglycolate phosphatase regulates central carbon metabolism and fosmidomycin sensitivity inPlasmodium falciparum

“…The high glycolytic flux of P. falciparum asexual stages provides these cells with sufficient ATP and biosynthetic precursors to sustain anabolic processes and high rates of replication. However, high rates of glycolysis can generate toxic metabolic end-products, such as methylglyoxal, which can lead to increased oxidative stress, chemical modification and denaturation/inactivation of proteins, lipids and DNA (6-8). Thus, it is likely that P. falciparum has evolved ways to regulate pathways such as glycolysis under nutrient excess conditions.…”

Epigenetic treatment of dermatologic disorders

“…This heightened expression helps to eliminate the buildup of tumorigenic cells in the epidermis in response to DNA damage‐inducing agents (Siegenthaler et al, ). The opposing, complementary functions of Nrf2 and Nrf3 further underscore a critical dilemma faced in arbitrarily overactivating Nrf2 (Dodson et al, ; Ikehata & Yamamoto, ; Menegon et al, ; Rabbani, Xue, et al, ; Silva‐Palacios et al, ; Sova & Saso, ).…”

“…Nrf2-modulating therapeutic, free from causing detrimental side effects, is the dilemma imposed by cellular Nrf2 expression levels that tend to vary significantly with age, tissue type, disease stage, immunocompetent status, and the insult being thwarted (Silva-Palacios, Ostolga-Chavarría, Zazueta, & Königsberg, 2018). For instance, induced Nrf2 activation is believed to be favorable in helping to prevent or delay the onset of neurodegenerative diseases and cancer (Al-Sawaf et al, 2015;Buendia et al, 2016;Dinkova-Kostova et al, 2018;Dodson et al, 2019;Loboda et al, 2016;Lu et al, 2016;Silva-Palacios et al, 2018;Sivandzade et al, 2019;Sova & Saso, 2018), while overactivation can progress tumorigenesis and accelerate metastasis (Badrinath & Yoo, 2018;Dodson et al, 2019;Menegon, Columbano, & Giordano, 2016;Rabbani, Xue, Weickert, & Thornalley, 2018;Sabharwal & Schumacker, 2014;Silva-Palacios et al, 2018;Sova & Saso, 2018). Interestingly, although many studies link decreased activity of Nrf2 in the elderly (as part of the aging process, particularly in the brain) to an increased prevalence of (neuro)degenerative diseases (Silva-Palacios et al, 2018;Sivandzade et al, 2019), the decreased activity may actually be serving a protective role against UV-induced carcinogenesis in skin (Siegenthaler et al, 2018).…”

“…The opposing, complementary functions of Nrf2 and Nrf3 further underscore a critical dilemma faced in arbitrarily overactivating Nrf2 (Dodson et al, 2019;Ikehata & Yamamoto, 2018;Menegon et al, 2016;Rabbani, Xue, et al, 2018;Silva-Palacios et al, 2018;Sova & Saso, 2018).…”