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

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

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aerobiosis
  • Breast Neoplasms / pathology*
  • Breast Neoplasms / physiopathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Glycation End Products, Advanced / metabolism*
  • Glycolysis*
  • Glycosylation
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Neoplasm Metastasis*
  • Phosphoproteins / metabolism*
  • Protein Processing, Post-Translational
  • Pyruvaldehyde / metabolism*
  • Transcription Factors
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Glycation End Products, Advanced
  • HSP90 Heat-Shock Proteins
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Pyruvaldehyde