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Elife. 2016 Oct 19;5. pii: e19375. doi: 10.7554/eLife.19375.

Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis.

Author information

1
Metastasis Research Laboratory, GIGA-CANCER, University of Liège, Liège, Belgium.
2
Mass Spectrometry Laboratory, GIGA-Systems Biology and Chemical Biology, University of Liège, Liège, Belgium.
3
GIGA Proteomic Facility, University of Liège, Liège, Belgium.
4
Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, Maastricht, Netherlands.
5
Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
6
Laboratory of Medicinal Chemistry - CIRM, University of Liège, Liège, Belgium.
7
Department of Pathology, CHU, University of Liège, Liège, Belgium.
8
Laboratory of Cellular and Tissular Biology, GIGA-Neurosciences, University of Liège, Liège, Belgium.
9
Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, University of Nagoya, Nagoya, Japan.
10
Department of Chemistry, Yale University, New Haven, United States.
11
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
12
Association for Research and Treatments Against Cancer, Paris, France.

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.

KEYWORDS:

LATS1; YAP; breast cancer; cancer biology; carbonyl stress; cell biology; chicken; glyoxalase 1; human; methylglyoxal; mouse

PMID:
27759563
PMCID:
PMC5081250
DOI:
10.7554/eLife.19375
[Indexed for MEDLINE]
Free PMC Article

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