[en] Metabolic reprogramming toward aerobic glycolysis unavoidably favours methylglyoxal (MG) and advanced glycation end products (AGEs) formation in cancer cells. MG was initially considered a highly cytotoxic molecule with potential anti-cancer value. However, we have recently demonstrated that MG enhanced tumour growth and metastasis. In an attempt to understand this dual role, we explored MG-mediated dicarbonyl stress status in four breast and glioblastoma cancer cell lines in relation with their glycolytic phenotype and MG detoxifying capacity. In glycolytic cancer cells cultured in high glucose, we observed a significant increase of the conversion of MG to D-lactate through the glyoxalase system. Moreover, upon exogenous MG challenge, glycolytic cells showed elevated amounts of intracellular MG and induced de novo GLO1 detoxifying enzyme and Nrf2 expression. Thus, supporting the adaptive nature of glycolytic cancer cells to MG dicarbonyl stress when compared to non-glycolytic ones. Finally and consistent with the pro-tumoural role of MG, we showed that low doses of MG induced AGEs formation and tumour growth in vivo, both of which can be reversed using a MG scavenger. Our study represents the first demonstration of a hormetic effect of MG defined by a low-dose stimulation and a high-dose inhibition of tumour growth.
Research Center/Unit :
Giga-Cancer - ULiège
Disciplines :
Oncology Microbiology
Author, co-author :
Nokin, Marie-Julie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Bellier, Justine ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Peulen, Olivier ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Uchida, Koji
Spiegel, David A.
Cochrane, James R.
Hutton, Craig A.
Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Bellahcene, Akeila ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Language :
English
Title :
Hormetic potential of methylglyoxal, a side-product of glycolysis, in switching tumours from growth to death.
Publication date :
2017
Journal title :
Scientific Reports
eISSN :
2045-2322
Publisher :
Nature Publishing Group, London, United Kingdom
Volume :
7
Issue :
1
Pages :
11722
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Télévie [BE] CAC - Centre anticancéreux près l'Université de Liège asbl [BE] ULiège FSR - Université de Liège. Fonds spéciaux pour la recherche [BE]
Ward, P. S. & Thompson, C. B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer cell 21, 297–308, 10.1016/j.ccr.2012.02.014 (2012)
Liberti, M. V. & Locasale, J. W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends in biochemical sciences 41, 211–218, 10.1016/j.tibs.2015.12.001 (2016)
Phillips, S. A. & Thornalley, P. J. The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. European journal of biochemistry / FEBS 212, 101–105 (1993)
Richard, J. P. Mechanism for the formation of methylglyoxal from triosephosphates. Biochemical Society transactions 21, 549–553 (1993)
Maessen, D. E., Stehouwer, C. D. & Schalkwijk, C. G. The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases. Clin Sci (Lond) 128, 839–861, 10.1042/CS20140683 (2015)
Ahmad, S. et al. Glycoxidation of biological macromolecules: a critical approach to halt the menace of glycation. Glycobiology 24, 979–990, 10.1093/glycob/cwu057 (2014)
Ahmad, S. et al. Genotoxicity and immunogenicity of DNA-advanced glycation end products formed by methylglyoxal and lysine in presence of Cu2 +. Biochemical and biophysical research communications 407, 568–574, 10.1016/j.bbrc.2011.03.064 (2011)
Rulli, A. et al. Expression of glyoxalase I and II in normal and breast cancer tissues. Breast cancer research and treatment 66, 67–72 (2001)
Bair, W. B. 3rd, Cabello, C. M., Uchida, K., Bause, A. S. & Wondrak, G. T. GLO1 overexpression in human malignant melanoma. Melanoma research 20, 85–96, 10.1097/CMR.0b013e3283364903 (2010)
Ranganathan, S. & Tew, K. D. Analysis of glyoxalase-I from normal and tumor tissue from human colon. Biochimica et biophysica acta 1182, 311–316 (1993)
Vander Jagt, D. L. & Hunsaker, L. A. Methylglyoxal metabolism and diabetic complications: roles of aldose reductase, glyoxalase-I, betaine aldehyde dehydrogenase and 2-oxoaldehyde dehydrogenase. Chemico-biological interactions 143–144, 341–351 (2003)
Nishimura, C., Furue, M., Ito, T., Omori, Y. & Tanimoto, T. Quantitative determination of human aldose reductase by enzyme-linked immunosorbent assay. Immunoassay of human aldose reductase. Biochem Pharmacol 46, 21–28 (1993)
Rabbani, N., Xue, M. & Thornalley, P. J. Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics. Glycoconjugate journal 33, 513–525, 10.1007/s10719-016-9705-z (2016)
Morgenstern, J. et al. Loss of glyoxalase 1 induces compensatory mechanism to achieve dicarbonyl detoxification in mammalian Schwann cells. The Journal of biological chemistry. 10.1074/jbc.M116.760132 (2016)
Apple, M. A. & Greenberg, D. M. Inhibition of cancer growth in mice by a normal metabolite. Life sciences 6, 2157–2160 (1967)
Jerzykowski, T., Matuszewski, W., Otrzonsek, N. & Winter, R. Antineoplastic action of methylglyoxal. Neoplasma 17, 25–35 (1970)
Conroy, P. J. Carcinostatic activity of methylglyoxal and related substances in tumour-bearing mice. Ciba Foundation symposium, 271-300 (1978)
Thornalley, P. J. et al. Antitumour activity of S-p-bromobenzylglutathione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis. Biochemical pharmacology 51, 1365–1372 (1996)
Lo, T. W. & Thornalley, P. J. Inhibition of proliferation of human leukaemia 60 cells by diethyl esters of glyoxalase inhibitors in vitro. Biochemical pharmacology 44, 2357–2363 (1992)
Sakamoto, H. et al. Selective activation of apoptosis program by S-p-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells. Clinical cancer research: an official journal of the American Association for Cancer Research 7, 2513–2518 (2001)
Santarius, T. et al. GLO1-A novel amplified gene in human cancer. Genes, chromosomes & cancer 49, 711–725, 10.1002/gcc.20784 (2010)
Chiavarina, B. et al. Triple negative tumors accumulate significantly less methylglyoxal specific adducts than other human breast cancer subtypes. Oncotarget (2014)
Chiavarina, B. et al. Methylglyoxal-Mediated Stress Correlates with High Metabolic Activity and Promotes Tumor Growth in Colorectal Cancer. International journal of molecular sciences 18, doi:10.3390/ijms18010213 (2017)
Nokin, M. J. et al. Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis. eLife 5, doi:10.7554/eLife.19375 (2016)
Bellahcene, A., Nokin, M. J., Castronovo, V. & Schalkwijk, C. Methylglyoxal-derived stress: an emerging biological factor involved in the onset and progression of cancer. Seminars in cancer biology, in press (2017)
Wang, T., Douglass, E. F. Jr., Fitzgerald, K. J. & Spiegel, D. A. A “turn-on” fluorescent sensor for methylglyoxal. Journal of the American Chemical Society 135, 12429–12433, 10.1021/ja406077j (2013)
Sejersen, H. & Rattan, S. I. Dicarbonyl-induced accelerated aging in vitro in human skin fibroblasts. Biogerontology 10, 203–211, 10.1007/s10522-008-9172-4 (2009)
Yao, D. & Brownlee, M. Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes 59, 249–255, 10.2337/db09-0801 (2010)
Kalapos, M. P. The tandem of free radicals and methylglyoxal. Chemico-biological interactions 171, 251–271, 10.1016/j.cbi.2007.11.009 (2008)
Du, J. et al. Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process. Free radical biology & medicine 31, 469–478 (2001)
Chang, T., Wang, R. & Wu, L. Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells. Free radical biology & medicine 38, 286–293, 10.1016/j.freeradbiomed.2004.10.034 (2005)
Figarola, J. L., Singhal, J., Rahbar, S., Awasthi, S. & Singhal, S. S. LR-90 prevents methylglyoxal-induced oxidative stress and apoptosis in human endothelial cells. Apoptosis: an international journal on programmed cell death 19, 776–788, 10.1007/s10495-014-0974-3 (2014)
Yuan, J. et al. The role of cPLA2 in Methylglyoxal-induced cell apoptosis of HUVECs. Toxicol Appl Pharmacol 323, 44–52, 10.1016/j.taap.2017.03.020 (2017)
Hay, N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nature reviews. Cancer 16, 635–649, 10.1038/nrc.2016.77 (2016)
Rabbani, N. & Thornalley, P. J. Measurement of methylglyoxal by stable isotopic dilution analysis LC-MS/MS with corroborative prediction in physiological samples. Nature protocols 9, 1969–1979, 10.1038/nprot.2014.129 (2014)
Lee, H. J., Howell, S. K., Sanford, R. J. & Beisswenger, P. J. Methylglyoxal can modify GAPDH activity and structure. Annals of the New York Academy of Sciences 1043, 135–145, 10.1196/annals.1333.017 (2005)
Beisswenger, P. & Ruggiero-Lopez, D. Metformin inhibition of glycation processes. Diabetes & metabolism 29, 6S95–103 (2003)
Zhang, J. Y. et al. Critical protein GAPDH and its regulatory mechanisms in cancer cells. Cancer Biol Med 12, 10–22, 10.7497/j.issn.2095-3941.2014.0019 (2015)
Xue, M. et al. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation. The Biochemical journal 443, 213–222, 10.1042/BJ20111648 (2012)
Nguyen, T., Nioi, P. & Pickett, C. B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284, 13291–13295, 10.1074/jbc.R900010200 (2009)
Le Calvé, B. et al. Long-term in vitro treatment of human glioblastoma cells with temozolomide increases resistance in vivo through up-regulation of GLUT transporter and aldo-keto reductase enzyme AKR1C expression. Neoplasia 12, 727–739 (2010)
Zhong, T., Xu, F., Xu, J., Liu, L. & Chen, Y. Aldo-keto reductase 1C3 (AKR1C3) is associated with the doxorubicin resistance in human breast cancer via PTEN loss. Biomed Pharmacother 69, 317–325, 10.1016/j.biopha.2014.12.022 (2015)
Mattson, M. P. Hormesis defined. Ageing research reviews 7, 1–7, 10.1016/j.arr.2007.08.007 (2008)
Radu, B. M., Dumitrescu, D. I., Mustaciosu, C. C. & Radu, M. Dual effect of methylglyoxal on the intracellular Ca2 + signaling and neurite outgrowth in mouse sensory neurons. Cellular and molecular neurobiology 32, 1047–1057, 10.1007/s10571-012-9823-5 (2012)
Menegon, S., Columbano, A. & Giordano, S. The Dual Roles of NRF2 in Cancer. Trends in molecular medicine 22, 578–593, 10.1016/j.molmed.2016.05.002 (2016)
Zender, L. et al. An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Cell 135, 852–864, 10.1016/j.cell.2008.09.061 (2008)
Antognelli, C., Mezzasoma, L., Fettucciari, K. & Talesa, V. N. A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells. The international journal of biochemistry & cell biology 45, 836–844, 10.1016/j.biocel.2013.01.003 (2013)
Hutschenreuther, A. et al. Modulation of GLO1 Expression Affects Malignant Properties of Cells. International journal of molecular sciences 17, doi:10.3390/ijms17122133 (2016)
Zhang, S. et al. Glo1 genetic amplification as a potential therapeutic target in hepatocellular carcinoma. International journal of clinical and experimental pathology 7, 2079–2090 (2014)
Taniguchi, H. et al. Targeting the glyoxalase pathway enhances TRAIL efficacy in cancer cells by downregulating the expression of antiapoptotic molecules. Molecular cancer therapeutics 11, 2294–2300, 10.1158/1535-7163.MCT-12-0031 (2012)
Hu, X., Yang, X., He, Q., Chen, Q. & Yu, L. Glyoxalase 1 is up-regulated in hepatocellular carcinoma and is essential for HCC cell proliferation. Biotechnology letters 36, 257–263, 10.1007/s10529-013-1372-6 (2014)
Hosoda, F. et al. Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer. Oncogene 34, 1196–1206, 10.1038/onc.2014.57 (2015)
Shen, Y. et al. Carnosine inhibits the proliferation of human gastric cancer SGC-7901 cells through both of the mitochondrial respiration and glycolysis pathways. PloS one 9, e104632, 10.1371/journal.pone.0104632 (2014)
Iovine, B. et al. The anti-proliferative effect of L-carnosine correlates with a decreased expression of hypoxia inducible factor 1 alpha in human colon cancer cells. PLoS One 9, e96755, 10.1371/journal.pone.0096755 (2014)
Jung, K. A. et al. Identification of aldo-keto reductases as NRF2-target marker genes in human cells. Toxicology letters 218, 39–49, 10.1016/j.toxlet.2012.12.026 (2013)
Jaffe, E. A., Nachman, R. L., Becker, C. G. & Minick, C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52, 2745–2756, 10.1172/JCI107470 (1973)
Oya, T. et al. Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts. The Journal of biological chemistry 274, 18492–18502 (1999)
Rahman, I., Kode, A. & Biswas, S. K. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 1, 3159–3165, 10.1038/nprot.2006.378 (2006)
