title: Methylglyoxal-Mediated Stress Correlates with High Metabolic Activity and Promotes Tumor Growth in Colorectal Cancer.
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 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.
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, 4000 Liège, Belgium. barbarachiavarina@libero.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Chiavarina
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, 4000 Liège, Belgium. mjnokin@ulg.ac.be.
authors.forename: Marie-Julie
authors.initials: MJ
authors.lastname: Nokin
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, 4000 Liège, Belgium. Justine.Bellier@ulg.ac.be.
authors.forename: Justine
authors.initials: J
authors.lastname: Bellier
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, 4000 Liège, Belgium. florence.durieux@student.ulg.ac.be.
authors.forename: Florence
authors.initials: F
authors.lastname: Durieux
authors.affiliation: Department of Pathology, Liège University Hospital, 4000 Liège, Belgium. nbletard@chu.ulg.ac.be.
authors.forename: Noëlla
authors.initials: N
authors.lastname: Bletard
authors.affiliation: Department of Nuclear Medicine, Erasme University Hospital, Université Libre de Bruxelles, 1050 Bruxelles, Belgium. fsherer@ulb.ac.be.
authors.forename: Félicie
authors.initials: F
authors.lastname: Sherer
authors.affiliation: Nuclear Medicine and Oncological Imaging Division, Medical Physics Department, Liège University Hospital, 4000 Liège, Belgium. pierre.lovinfosse@chu.ulg.ac.be.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lovinfosse
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, 4000 Liège, Belgium. Olivier.Peulen@ulg.ac.be.
authors.forename: Olivier
authors.initials: O
authors.lastname: Peulen
authors.affiliation: Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, 1050 Bruxelles, Belgium. Laurine.Verset@erasme.ulb.ac.be.
authors.forename: Laurine
authors.initials: L
authors.lastname: Verset
authors.affiliation: Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, 1050 Bruxelles, Belgium. Romain.Dehon@erasme.ulb.ac.be.
authors.forename: Romain
authors.initials: R
authors.lastname: Dehon
authors.affiliation: Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, 1050 Bruxelles, Belgium. Pieter.Demetter@erasme.ulb.ac.be.
authors.forename: Pieter
authors.initials: P
authors.lastname: Demetter
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, 4000 Liège, Belgium. A.Turtoi@ulg.ac.be.
authors.forename: Andrei
authors.initials: A
authors.lastname: Turtoi
authors.affiliation: Laboratory of Food Chemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 13-8654, Japan. a-uchida@mail.ecc.u-tokyo.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Nuclear Medicine, Erasme University Hospital, Université Libre de Bruxelles, 1050 Bruxelles, Belgium. sgoldman@ulb.ac.be.
authors.forename: Serge
authors.initials: S
authors.lastname: Goldman
authors.affiliation: Nuclear Medicine and Oncological Imaging Division, Medical Physics Department, Liège University Hospital, 4000 Liège, Belgium. rhustinx@chu.ulg.ac.be.
authors.forename: Roland
authors.initials: R
authors.lastname: Hustinx
authors.affiliation: Department of Pathology, Liège University Hospital, 4000 Liège, Belgium. P.Delvenne@ulg.ac.be.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, 4000 Liège, Belgium. vcastronovo@ulg.ac.be.
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, 4000 Liège, Belgium. a.bellahcene@ulg.ac.be.
authors.forename: Akeila
authors.initials: A
authors.lastname: Bellahcène
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002336:Carnosine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019788:Fluorodeoxyglucose F18; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D011743:Pyrimidines; D019788:Fluorodeoxyglucose F18; D011765:Pyruvaldehyde; D002336:Carnosine; C000597196:GLO1 protein, human; D007791:Lactoylglutathione Lyase; C030986:pyrimidine
keywords: 18F-Fluorodeoxyglucose (18F-FDG); MG-adducts; colorectal cancer; glyoxalase 1; methylglyoxal