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Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization
William J Sullivan1, Peter J Mullen2, Ernst W Schmid2
1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Cell
|September 11, 2018
Summary
Extracellular matrix remodeling regulates cellular metabolism. Hyaluronidase treatment increases glycolysis by degrading TXNIP, enhancing glucose transporter GLUT1 at the cell surface, and promoting cell migration.
Area of Science:
- Cell Biology
- Biochemistry
- Cancer Research
Background:
- Cellular metabolism is influenced by external factors like nutrients and growth signals.
- Extracellular matrix (ECM) remodeling is identified as a key regulator of cell-extrinsic metabolic control.
Purpose of the Study:
- To investigate the role of ECM remodeling in regulating cellular metabolism.
- To identify specific molecular mechanisms linking ECM components to metabolic pathways.
Main Methods:
- Unbiased analysis of glycolytic drivers in cancer cells.
- Treatment of cells and xenografts with hyaluronidase.
- Analysis of receptor tyrosine kinase signaling and mRNA decay factors.
- Assessment of glucose transporter GLUT1 localization and function.
- Evaluation of cell migration assays.
Main Results:
- Hyaluronan-mediated motility receptor strongly correlates with glycolysis in cancer.
- Hyaluronidase treatment significantly increases glycolysis.
- This increase is mediated by ZFP36 induction, targeting TXNIP for degradation.
- Reduced TXNIP leads to increased GLUT1 at the plasma membrane, enhancing glucose uptake.
- Hyaluronidase-induced glycolysis is essential for accelerated cell migration.
Conclusions:
- ECM remodeling, specifically hyaluronan degradation, directly impacts cellular metabolism by modulating glycolysis.
- The identified pathway involving hyaluronan-mediated motility receptor, ZFP36, TXNIP, and GLUT1 provides a novel mechanism linking ECM to metabolism.
- This metabolic regulation by ECM is crucial in dynamic biological processes such as tumorigenesis and embryogenesis.
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