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http://dx.doi.org/10.14348/molcells.2022.0109

Glyoxalase 1 as a Therapeutic Target in Cancer and Cancer Stem Cells  

Ji-Young, Kim (Department of Internal Medicine, School of Medicine, Kangwon National University)
Ji-Hye, Jung (Department of Internal Medicine, School of Medicine, Kangwon National University)
Seung-Joon, Lee (Department of Internal Medicine, School of Medicine, Kangwon National University)
Seon-Sook, Han (Department of Internal Medicine, School of Medicine, Kangwon National University)
Seok-Ho, Hong (Department of Internal Medicine, School of Medicine, Kangwon National University)
Publication Information
Molecules and Cells / v.45, no.12, 2022 , pp. 869-876 More about this Journal
Abstract
Methylglyoxal (MG) is a dicarbonyl compound formed in cells mainly by the spontaneous degradation of the triose phosphate intermediates of glycolysis. MG is a powerful precursor of advanced glycation end products, which lead to strong dicarbonyl and oxidative stress. Although divergent functions of MG have been observed depending on its concentration, MG is considered to be a potential antitumor factor due to its cytotoxic effects within the oncologic domain. MG detoxification is carried out by the glyoxalase system. Glyoxalase 1 (Glo1), the ubiquitous glutathionedependent enzyme responsible for MG degradation, is considered to be a tumor promoting factor due to it catalyzing the removal of cytotoxic MG. Indeed, various cancer types exhibit increased expression and activity of Glo1 that closely correlate with tumor cell growth and metastasis. Furthermore, mounting evidence suggests that Glo1 contributes to cancer stem cell survival. In this review, we discuss the role of Glo1 in the malignant progression of cancer and its possible use as a promising therapeutic target for tumor therapy. We also summarize therapeutic outcomes of Glo1 inhibitors as prospective treatments for the prevention of cancer.
Keywords
cancer; cancer stem cell; glyoxalase 1; methylglyoxal;
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1 Chiavarina, B., Nokin, M.J., Durieux, F., Bianchi, E., Turtoi, A., Peulen, O., Peixoto, P., Irigaray, P., Uchida, K., Belpomme, D., et al. (2014). Triple negative tumors accumulate significantly less methylglyoxal specific adducts than other human breast cancer subtypes. Oncotarget 5, 5472-5482.   DOI
2 Ciocca, D.R. and Calderwood, S.K. (2005). Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10, 86-103.
3 Doherty, C., Delahunt, E., Caulfield, B., Hertel, J., Ryan, J., and Bleakley, C. (2014). The incidence and prevalence of ankle sprain injury: a systematic review and meta-analysis of prospective epidemiological studies. Sports Med. 44, 123-140.
4 Elston, C.W. and Ellis, I.O. (1991). Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19, 403-410.   DOI
5 Ferreira, L.M. (2010). Cancer metabolism: the Warburg effect today. Exp. Mol. Pathol. 89, 372-380.   DOI
6 Finkelstein, M.P., Aynehchi, S., Samadi, A.A., Drinis, S., Choudhury, M.S., Tazaki, H., and Konno, S. (2002). Chemosensitization of carmustine with maitake beta-glucan on androgen-independent prostatic cancer cells: involvement of glyoxalase I. J. Altern. Complement. Med. 8, 573-580.   DOI
7 Fonseca-Sanchez, M.A., Rodriguez Cuevas, S., Mendoza-Hernandez, G., Bautista-Pina, V., Arechaga Ocampo, E., Hidalgo Miranda, A., Quintanar Jurado, V., Marchat, L.A., Alvarez-Sanchez, E., Perez Plasencia, C., et al. (2012). Breast cancer proteomics reveals a positive correlation between glyoxalase 1 expression and high tumor grade. Int. J. Oncol. 41, 670-680.   DOI
8 Guo, Y., Zhang, Y., Yang, X., Lu, P., Yan, X., Xiao, F., Zhou, H., Wen, C., Shi, M., Lu, J., et al. (2016). Effects of methylglyoxal and glyoxalase I inhibition on breast cancer cells proliferation, invasion, and apoptosis through modulation of MAPKs, MMP9, and Bcl-2. Cancer Biol. Ther. 17, 169-180.   DOI
9 Hara, T., Toyoshima, M., Hisano, Y., Balan, S., Iwayama, Y., Aono, H., Futamura, Y., Osada, H., Owada, Y., and Yoshikawa, T. (2021). Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons. Transl. Psychiatry 11, 275.
10 Hosoda, F., Arai, Y., Okada, N., Shimizu, H., Miyamoto, M., Kitagawa, N., Katai, H., Taniguchi, H., Yanagihara, K., Imoto, I., et al. (2015). Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer. Oncogene 34, 1196-1206.   DOI
11 Hu, X., Yang, X., He, Q., Chen, Q., and Yu, L. (2014). Glyoxalase 1 is upregulated in hepatocellular carcinoma and is essential for HCC cell proliferation. Biotechnol. Lett. 36, 257-263.   DOI
12 Jandial, R., Neman, J., Lim, P.P., Tamae, D., Kowolik, C.M., Wuenschell, G.E., Shuck, S.C., Ciminera, A.K., De Jesus, L.R., Ouyang, C., et al. (2018). Inhibition of GLO1 in glioblastoma multiforme increases DNA-AGEs, stimulates RAGE expression, and inhibits brain tumor growth in orthotopic mouse models. Int. J. Mol. Sci. 19, 406.
13 Koh, E.Y., You, J.E., Jung, S.H., and Kim, P.H. (2020). Biological functions and identification of novel biomarker expressed on the surface of breast cancer-derived cancer stem cells via proteomic analysis. Mol. Cells 43, 384-396.   DOI
14 Kreycy, N., Gotzian, C., Fleming, T., Flechtenmacher, C., Grabe, N., Plinkert, P., Hess, J., and Zaoui, K. (2017). Glyoxalase 1 expression is associated with an unfavorable prognosis of oropharyngeal squamous cell carcinoma. BMC Cancer 17, 382.
15 Milanesa, D.M., Choudhury, M.S., Mallouh, C., Tazaki, H., and Konno, S. (2000). Methylglyoxal-induced apoptosis in human prostate carcinoma: potential modality for prostate cancer treatment. Eur. Urol. 37, 728-734.   DOI
16 Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M.A., and Dick, J.E. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645-648.   DOI
17 Loarca, L., Sassi-Gaha, S., and Artlett, C.M. (2013). Two alpha-dicarbonyls downregulate migration, invasion, and adhesion of liver cancer cells in a p53-dependent manner. Dig. Liver Dis. 45, 938-946.   DOI
18 Michel, M., Hollenbach, M., Pohl, S., Ripoll, C., and Zipprich, A. (2019). Inhibition of glyoxalase-I leads to reduced proliferation, migration and colony formation, and enhanced susceptibility to sorafenib in hepatocellular carcinoma. Front. Oncol. 9, 785.
19 Motomura, H., Ozaki, A., Tamori, S., Onaga, C., Nozaki, Y., Waki, Y., Takasawa, R., Yoshizawa, K., Mano, Y., Sato, T., et al. (2021a). Glyoxalase 1 and protein kinase Clambda as potential therapeutic targets for late-stage breast cancer. Oncol. Lett. 22, 547.
20 Motomura, H., Tamori, S., Yatani, M.A., Namiki, A., Onaga, C., Ozaki, A., Takasawa, R., Mano, Y., Sato, T., Hara, Y., et al. (2021b). GLO 1 and PKClambda regulate ALDH1-positive breast cancer stem cell survival. Anticancer Res. 41, 5959-5971.   DOI
21 Movahed, Z.G., Yarani, R., Mohammadi, P., and Mansouri, K. (2021). Sustained oxidative stress instigates differentiation of cancer stem cells into tumor endothelial cells: Pentose phosphate pathway, reactive oxygen species and autophagy crosstalk. Biomed. Pharmacother. 139, 111643.
22 Reya, T., Morrison, S.J., Clarke, M.F., and Weissman, I.L. (2001). Stem cells, cancer, and cancer stem cells. Nature 414, 105-111.   DOI
23 Nokin, M.J., Bellier, J., Durieux, F., Peulen, O., Rademaker, G., Gabriel, M., Monseur, C., Charloteaux, B., Verbeke, L., van Laere, S., et al. (2019). Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer. Breast Cancer Res. 21, 11.
24 Nokin, M.J., Durieux, F., Peixoto, P., Chiavarina, B., Peulen, O., Blomme, A., Turtoi, A., Costanza, B., Smargiasso, N., Baiwir, D., et al. (2016). Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis. Elife 5, e19375.
25 Park, J., Kim, J.S., Nahm, J.H., Kim, S.K., Lee, D.H., and Lim, D.S. (2020). WWC1 and NF2 prevent the development of intrahepatic cholangiocarcinoma by regulating YAP/TAZ activity through LATS in mice. Mol. Cells 43, 491-499.   DOI
26 Sakamoto, H., Mashima, T., Kizaki, A., Dan, S., Hashimoto, Y., Naito, M., and Tsuruo, T. (2000). Glyoxalase I is involved in resistance of human leukemia cells to antitumor agent-induced apoptosis. Blood 95, 3214-3218.   DOI
27 Ricardo, S., Vieira, A.F., Gerhard, R., Leitao, D., Pinto, R., Cameselle-Teijeiro, J.F., Milanezi, F., Schmitt, F., and Paredes, J. (2011). Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J. Clin. Pathol. 64, 937-946.   DOI
28 Rounds, L., Nagle, R.B., Muranyi, A., Jandova, J., Gill, S., Vela, E., and Wondrak, G.T. (2021). Glyoxalase 1 expression as a novel diagnostic marker of high-grade prostatic intraepithelial neoplasia in prostate cancer. Cancers (Basel) 13, 3608.
29 Rulli, A., Carli, L., Romani, R., Baroni, T., Giovannini, E., Rosi, G., and Talesa, V. (2001). Expression of glyoxalase I and II in normal and breast cancer tissues. Breast Cancer Res. Treat. 66, 67-72.   DOI
30 Sakamoto, H., Mashima, T., Sato, S., Hashimoto, Y., Yamori, T., and Tsuruo, T. (2001). Selective activation of apoptosis program by S-p-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells. Clin. Cancer Res. 7, 2513-2518.
31 Sakamoto, H., Mashima, T., Yamamoto, K., and Tsuruo, T. (2002). Modulation of heat-shock protein 27 (Hsp27) anti-apoptotic activity by methylglyoxal modification. J. Biol. Chem. 277, 45770-45775.   DOI
32 Sousa Silva, M., Gomes, R.A., Ferreira, A.E., Ponces Freire, A., and Cordeiro, C. (2013). The glyoxalase pathway: the first hundred years... and beyond. Biochem. J. 453, 1-15.   DOI
33 Santarius, T., Bignell, G.R., Greenman, C.D., Widaa, S., Chen, L., Mahoney, C.L., Butler, A., Edkins, S., Waris, S., Thornalley, P.J., et al. (2010). GLO1-A novel amplified gene in human cancer. Genes Chromosomes Cancer 49, 711-725.   DOI
34 Santel, T., Pflug, G., Hemdan, N.Y., Schafer, A., Hollenbach, M., Buchold, M., Hintersdorf, A., Lindner, I., Otto, A., Bigl, M., et al. (2008). Curcumin inhibits glyoxalase 1: a possible link to its anti-inflammatory and anti-tumor activity. PLoS One 3, e3508.
35 Shimada, N., Takasawa, R., and Tanuma, S.I. (2018). Interdependence of GLO I and PKM2 in the Metabolic shift to escape apoptosis in GLO I-dependent cancer cells. Arch. Biochem. Biophys. 638, 1-7.   DOI
36 Takasawa, R., Shimada, N., Uchiro, H., Takahashi, S., Yoshimori, A., and Tanuma, S. (2016). TLSC702, a novel inhibitor of human glyoxalase I, induces apoptosis in tumor cells. Biol. Pharm. Bull. 39, 869-873.   DOI
37 Takeuchi, M., Kimura, S., Kuroda, J., Ashihara, E., Kawatani, M., Osada, H., Umezawa, K., Yasui, E., Imoto, M., Tsuruo, T., et al. (2010). Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment. Cell Death Differ. 17, 1211-1220.   DOI
38 Tamori, S., Nozaki, Y., Motomura, H., Nakane, H., Katayama, R., Onaga, C., Kikuchi, E., Shimada, N., Suzuki, Y., Noike, M., et al. (2018). Glyoxalase 1 gene is highly expressed in basal-like human breast cancers and contributes to survival of ALDH1-positive breast cancer stem cells. Oncotarget 9, 36515-36529.   DOI
39 Thornalley, P.J. (2003). Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy. Biochem. Soc. Trans. 31, 1372-1377.   DOI
40 Taniguchi, H., Horinaka, M., Yoshida, T., Yano, K., Goda, A.E., Yasuda, S., Wakada, M., and Sakai, T. (2012). Targeting the glyoxalase pathway enhances TRAIL efficacy in cancer cells by downregulating the expression of antiapoptotic molecules. Mol. Cancer Ther. 11, 2294-2300.   DOI
41 Thornalley, P.J., Edwards, L.G., Kang, Y., Wyatt, C., Davies, N., Ladan, M.J., and Double, J. (1996). Antitumour activity of S-p-bromobenzylglutathione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis. Biochem. Pharmacol. 51, 1365-1372.   DOI
42 Thornalley, P.J. and Rabbani, N. (2011). Glyoxalase in tumourigenesis and multidrug resistance. Semin. Cell Dev. Biol. 22, 318-325.   DOI
43 Thornalley, P.J., Waris, S., Fleming, T., Santarius, T., Larkin, S.J., WinklhoferRoob, B.M., Stratton, M.R., and Rabbani, N. (2010). Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance. Nucleic Acids Res. 38, 5432-5442.   DOI
44 Visvader, J.E. and Lindeman, G.J. (2012). Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10, 717-728.   DOI
45 Vulesevic, B., McNeill, B., Geoffrion, M., Kuraitis, D., McBane, J.E., Lochhead, M., Vanderhyden, B.C., Korbutt, G.S., Milne, R.W., and Suuronen, E.J. (2014). Glyoxalase-1 overexpression in bone marrow cells reverses defective neovascularization in STZ-induced diabetic mice. Cardiovasc. Res. 101, 306-316.   DOI
46 Zhang, S., Gao, Q., Li, W., Zhu, L., Shang, Q., Feng, S., Jia, J., Jia, Q., Shen, S., and Su, Z. (2019). Shikonin inhibits cancer cell cycling by targeting Cdc25s. BMC Cancer 19, 20.
47 Walcher, L., Kistenmacher, A.K., Suo, H., Kitte, R., Dluczek, S., Strauss, A., Blaudszun, A.R., Yevsa, T., Fricke, S., and Kossatz-Boehlert, U. (2020). Cancer stem cells-origins and biomarkers: perspectives for targeted personalized therapies. Front. Immunol. 11, 1280.
48 Xue, M., Rabbani, N., Momiji, H., Imbasi, P., Anwar, M.M., Kitteringham, N., Park, B.K., Souma, T., Moriguchi, T., Yamamoto, M., et al. (2012). Transcriptional control of glyoxalase 1 by Nrf2 provides a stressresponsive defence against dicarbonyl glycation. Biochem. J. 443, 213-222.   DOI
49 Yang, G., Cancino, G.I., Zahr, S.K., Guskjolen, A., Voronova, A., Gallagher, D., Frankland, P.W., Kaplan, D.R., and Miller, F.D. (2016). A Glo1-methylglyoxal pathway that is perturbed in maternal diabetes regulates embryonic and adult neural stem cell pools in murine offspring. Cell Rep. 17, 1022-1036.   DOI
50 Zhang, X., Jiang, Y., Huang, Q., Wu, Z., Pu, H., Xu, Z., Li, B., Lu, X., Yang, X., Qin, J., et al. (2021). Exosomes derived from adipose-derived stem cells overexpressing glyoxalase-1 protect endothelial cells and enhance angiogenesis in type 2 diabetic mice with limb ischemia. Stem Cell Res. Ther. 12, 403.
51 Zhang, X., Zhao, H., Li, Y., Xia, D., Yang, L., Ma, Y., and Li, H. (2018). The role of YAP/TAZ activity in cancer metabolic reprogramming. Mol. Cancer 17, 134.
52 Zou, X.Y., Ding, D., Zhan, N., Liu, X.M., Pan, C., and Xia, Y.M. (2015). Glyoxalase I is differentially expressed in cutaneous neoplasms and contributes to the progression of squamous cell carcinoma. J. Invest. Dermatol. 135, 589-598.   DOI
53 Bonnet, D. and Dick, J.E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730-737.   DOI
54 Alhujaily, M., Abbas, H., Xue, M., de la Fuente, A., Rabbani, N., and Thornalley, P.J. (2021). Studies of glyoxalase 1-linked multidrug resistance reveal glycolysis-derived reactive metabolite, methylglyoxal, is a common contributor in cancer chemotherapy targeting the spliceosome. Front. Oncol. 11, 748698.
55 Antognelli, C., Mandarano, M., Prosperi, E., Sidoni, A., and Talesa, V.N. (2021). Glyoxalase-1-dependent methylglyoxal depletion sustains PDL1 expression in metastatic prostate cancer cells: a novel mechanism in cancer immunosurveillance escape and a potential novel target to overcome PD-L1 blockade resistance. Cancers (Basel) 13, 2965.
56 Antognelli, C., Palumbo, I., Aristei, C., and Talesa, V.N. (2014). Glyoxalase I inhibition induces apoptosis in irradiated MCF-7 cells via a novel mechanism involving Hsp27, p53 and NF-kappaB. Br. J. Cancer 111, 395-406.   DOI
57 Chen, Y., Fang, L., Zhang, J., Li, G., Ma, M., Li, C., Lyu, J., and Meng, Q.H. (2017). 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. Int. J. Mol. Sci. 18, 570.
58 Cheng, W.L., Tsai, M.M., Tsai, C.Y., Huang, Y.H., Chen, C.Y., Chi, H.C., Tseng, Y.H., Chao, I.W., Lin, W.C., Wu, S.M., et al. (2012). Glyoxalase-I is a novel prognosis factor associated with gastric cancer progression. PLoS One 7, e34352.
59 Chiavarina, B., Nokin, M.J., Bellier, J., Durieux, F., Bletard, N., Sherer, F., Lovinfosse, P., Peulen, O., Verset, L., Dehon, R., et al. (2017). Methylglyoxalmediated stress correlates with high metabolic activity and promotes tumor growth in colorectal cancer. Int. J. Mol. Sci. 18, 213.