Targeting Chondroitin Sulfate Reduces Invasiveness of Glioma Cells by Suppressing CD44 and Integrin β1 Expression

Abstract

Chondroitin sulfate (CS) is a major component of the extracellular matrix found to be abnormally accumulated in several types of cancer tissues. Previous studies have indicated that CS synthases and modification enzymes are frequently elevated in human gliomas and are associated with poor prognosis. However, the underlying mechanisms of CS in cancer progression and approaches for interrupting its functions in cancer cells remain largely unexplored. Here, we have found that CS was significantly enriched surrounding the vasculature in a subset of glioma tissues, which was akin to the perivascular niche for cancer-initiating cells. Silencing or overexpression of the major CS synthase, chondroitin sulfate synthase 1 (CHSY1), significantly regulated the glioma cell invasive phenotypes and modulated integrin expression. Furthermore, we identified CD44 as a crucial chondroitin sulfate proteoglycan (CSPG) that was modified by CHSY1 on glioma cells, and the suppression of CS formation on CD44 by silencing the CHSY1-inhibited interaction between CD44 and integrin β1 on the adhesion complex. Moreover, we tested the CS-specific binding peptide, resulting in the suppression of glioma cell mobility in a fashion similar to that observed upon the silencing of CHSY1. In addition, the peptide demonstrated significant affinity to CD44, promoted CD44 degradation, and suppressed integrin β1 expression in glioma cells. Overall, this study proposes a potential regulatory loop between CS, CD44, and integrin β1 in glioma cells, and highlights the importance of CS in CD44 stability. Furthermore, the targeting of CS by specific binding peptides has potential as a novel therapeutic strategy for glioma.

Single cell spatial analysis identifies regulators of brain tumor initiating cells

“…Upregulation of genes encoding CSPGs including versican and CSPG4 was also observed in the GBM microenvironment compared to normal tissues. Other studies, like ours, have shown higher levels of CSPGs in GBM tissues than in normal brains 26, 27 . Also, expression of CSPGs and enzymes involved in chondroitin sulphate polymerization is elevated in the GBM microenvironment and corresponds with high tumor grade and poor survival 28–30 .…”

Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy

“…The experiment was repeated three times. Meanwhile, many research reported that hyaluronic acid (HA) and chondroitin sulfate (CS) could bind specifically with CD44 receptor 26 , 27 . To examine the uptake of CS/BH NPs was mediated by CD-44 receptors, cells were pretreated with excess free CS (5 mg/mL) or HA (5 mg/mL) for 1 h, respectively, then incubated with CS/BH NPs.…”

EPDR1 is a noncanonical effector of insulin-mediated angiogenesis regulated by an endothelial-specific TGF-β receptor complex

“…Indeed, while research has shown that hyperinsulinemia mediates pathologic angiogenesis through the proliferative actions of the ERK MAPK pathway ( 42 , 43 ), chronically elevated levels of insulin may also trigger the expression of EPDR1 and potentially many others through the endoglin/ALK1/Smad1/5 signaling axis. For instance, chondroitin sulfate synthase 2 ( 44 , 45 ) and prostaglandin F2 receptor-associated protein ( 46 , 47 , 48 ) are two of the top hits ranked higher than EPDR1, whereas others, including osteopontin ( 49 , 50 ) and platelet-derived growth factor receptor beta ( 51 , 52 ), represent promising candidates ranked slightly lower based on several parameters including fold changes over negative control and unique peptide counts identified ( Fig. S3 B ).…”