Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis
- University of Liège, Belgium
- Maastricht University, Netherlands
- University of Nagoya, Japan
- Yale University, United States
- University of Melbourne, Australia
- Université de Liège, Belgium
- University of LIège, Belgium
- Association for Research and Treatments Against Cancer, 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.
Data availability
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ER-positive/HER2-negative and ER-negative/HER2-negative breast cancer biopsies (MDACC/IGR cohort)Publicly available at the NCBI Gene Expression Omnibus (accession no: GDS4057) .
Article and author information
Author details
Funding
Université de Liège
- Akeila Bellahcène
MJN, FD and BCo are Télévie Fellows, BCh, ABl and AT are Télévie Post-Doctoral Fellows, PDT and ABe are Senior Research Associates, all from the National Fund for Scientific Research (FNRS, Belgium). This work was also supported by the Centre Anti-Cancéreux, University of Liège, Belgium.The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experimental procedures were performed according to the Federation of European Laboratory Animal Sciences Associations (FELASA) and were reviewed and approved by the Institutional Animal Care and Ethics Committee of the University of Liege, Belgium (#14-1714). All surgery was performed under ketamin/xylazine anesthesia, and every effort was made to minimize suffering.
Human subjects: Human breast tumor tissues were obtained from the Pathology Department of the University Hospital of Liege in agreement with ethical guidelines of the University of Liege, Belgium (#2015-155).
Copyright
© 2016, Nokin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis
eLife 5:e19375.
https://doi.org/10.7554/eLife.19375
