title: Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis.
abstract: Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment.
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Marie-Julie
authors.initials: MJ
authors.lastname: Nokin
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Florence
authors.initials: F
authors.lastname: Durieux
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Peixoto
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Chiavarina
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Peulen
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Blomme
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Andrei
authors.initials: A
authors.lastname: Turtoi
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Brunella
authors.initials: B
authors.lastname: Costanza
authors.affiliation: Mass Spectrometry Laboratory, GIGA-Systems Biology and Chemical Biology, University of Liège, Liège, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Smargiasso
authors.affiliation: GIGA Proteomic Facility, University of Liège, Liège, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Baiwir
authors.affiliation: Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, Maastricht, Netherlands.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Scheijen
authors.affiliation: Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, Maastricht, Netherlands.|Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: Laboratory of Medicinal Chemistry - CIRM, University of Liège, Liège, Belgium.
authors.forename: Justine
authors.initials: J
authors.lastname: Leenders
authors.affiliation: Laboratory of Medicinal Chemistry - CIRM, University of Liège, Liège, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: De Tullio
authors.affiliation: Department of Pathology, CHU, University of Liège, Liège, Belgium.
authors.forename: Elettra
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Laboratory of Cellular and Tissular Biology, GIGA-Neurosciences, University of Liège, Liège, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Thiry
authors.affiliation: Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, University of Nagoya, Nagoya, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Chemistry, Yale University, New Haven, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Spiegel
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: James R
authors.identifier: http://orcid.org/0000-0002-8796-2143
authors.initials: JR
authors.lastname: Cochrane
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Hutton
authors.affiliation: Mass Spectrometry Laboratory, GIGA-Systems Biology and Chemical Biology, University of Liège, Liège, Belgium.
authors.forename: Edwin
authors.initials: E
authors.lastname: De Pauw
authors.affiliation: Department of Pathology, CHU, University of Liège, Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Association for Research and Treatments Against Cancer, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Belpomme
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
authors.affiliation: Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
authors.forename: Akeila
authors.initials: A
authors.lastname: Bellahcène
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000332:Aerobiosis; D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006019:Glycolysis; D006031:Glycosylation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011765:Pyruvaldehyde / Q000378:metabolism*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017127:Glycation End Products, Advanced; D018841:HSP90 Heat-Shock Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D011765:Pyruvaldehyde
keywords: LATS1; YAP; breast cancer; cancer biology; carbonyl stress; cell biology; chicken; glyoxalase 1; human; methylglyoxal; mouse