Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization

Abstract

The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of the mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Because TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.

Secreted Protein Acidic and Rich in Cysteine: Metabolic and Homeostatic Properties beyond the Extracellular Matrix Structure

“…In addition, there is a possible link between the ECM and the mitochondrial function [41], which reflects other possible metabolic implications. At the molecular level, studies indicated how ECM (or its remodeling) regulates lipid metabolism [42] and glucose metabolism [43]. Moreover, the ECM-associated protein SPARC has been shown to be implicated in the regulation of the glucose transporter type 4 expression (controlling the glucose uptake) [44].…”

Tension in tumour cells keeps metabolism high

“…Together, Park and colleagues' data add to a growing body of evidence demonstrating how the composition of and changes in the ECM can modulate glucose metabolism 5,6 . The data also offer a potential explanation for the aberrant glucose regulation reported in meta bolically dysfunctional fatty breast tissue of people who are obese, in which the connec tive tissue, called the stroma, is often stiff 7 .…”

“…Although little is known about the initial target of eH 2 O 2 , the consequences of its pro duction are much better defined 4 . It is clear that eH 2 O 2 triggers an influx of calcium ions (Ca 2+ ) into the cell, which then leads to the sys temic transmission of signals between cells in waves, activating processes such as pathogen resistance or acclimation to stress across the entire plant 5 . In addition, eH 2 O 2 signals regu late the polarized growth of pollen tubes and root hairs 6 , and control the opening and clos ing of stomata 3 -pores on the outer layer of the leaf formed by two guard cells.…”

Cross-Talk Between the Tumor Microenvironment, Extracellular Matrix, and Cell Metabolism in Cancer

“…Recent data indicate that the degradation of hyaluronan, a ubiquitous ECM component, promotes glucose uptake in several cancer cell lines, by increasing the plasma membrane localization of the glucose transporter GLUT1. This in turns fosters glycolysis and promotes cancer cell migration (31). It is unclear whether the degradation of other ECM components is also linked to changes in cell metabolism.…”