Heparan Sulfate-Instructed Self-Assembly Selectively Inhibits Cancer Cell Migration

Abstract

Heparan sulfate (HS) has important emerging roles in oncogenesis, which represents potential therapeutic strategies for human cancers. However, due to the complexity of the HS signaling network, HS-targeted synthetic cancer therapeutics has never been successfully devised. To conquer the challenge, we developed HS-instructed self-assembling peptides by decorating the "Cardin−Weintraub" sequence with aromatic amino acids. The HS-binding interactions induce localized accumulation of synthetic peptides triggering molecular self-assembly in the vicinity of highly expressed Heparan sulfate proteoglycans (HSPGs) on the cancer cell membrane. The nanostructures hinder the binding of HSPG with metastasis promoting protein−heparin-binding EGF-like growth factor (HBEGF) inhibiting the activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Our study proved that HS-instructed self-assembly is a promising synthetic therapeutic strategy for targeted cancer migration inhibition.

Constructing ECM-like Structure on the Plasma Membrane via Peptide Assembly to Regulate the Cellular Response

“…(B3) TEM images of FFFFF-KRSR in the absence or presence of heparin. (B4) Wound-healing assay of co-cultured PANC-1-GFP/HS-5 cells upon the treatment of FFFFF-KRSR for 32 h. Reproduced with permission from ref . Copyright 2021 American Chemical Society.…”

“…As elucidated in Figure B, a well-designed peptide that selectively binds to HS will facilitate a localized accumulation triggering peptide assembly in the vicinity of HSPGs. The formed nanobiointerface on the plasma membrane hinders the interaction between HB-EGF and HSPG, inhibiting cancer cell migration . Three cationic peptide sequences including Phe-His-Arg-Arg-Ile-Lys-Ala (FHRRIKA), Lys-Arg-Ser-Arg (KRSR), and Leu-Arg-Lys-Lys-Leu-Gly-Lys-Ala (LRKKLGKA) that contain multiple lysine/arginine residues with the reported heparin-binding function were selected as HS-binding motifs.…”

“…The formed nanobiointerface on the plasma membrane hinders the interaction between HB-EGF and HSPG, inhibiting cancer cell migration. 98 Three cationic peptide sequences including Phe-His-Arg-Arg-Ile-Lys-Ala (FHRRIKA), Lys-Arg-Ser-Arg (KRSR), and Leu-Arg-Lys-Lys-Leu-Gly-Lys-Ala (LRKKLGKA) that contain multiple lysine/arginine residues with the reported heparin-binding function were selected as HSbinding motifs. Because of the highly hydrophilic nature of the HS-binding motifs, four or five phenylalanine repeats were incorporated to balance the hydrophilicity of the synthetic peptides promoting molecular self-assembly.…”

Self-Assembly of Small Organic Molecules into Luminophores for Cancer Theranostic Applications

“…[ 37 ]. Recently, a study showed that heparan sulfate (HS)-instructed self-assembled peptides hinder the interaction between heparin-binding EGF-like growth factor (HB-EGF) and heparan sulfate proteoglycans (HSPG), thus inhibiting cancer cell migration [ 38 ]. it is therefore an effective way to inhibit the metastasis of malignant tumors and inspires researchers to explore therapeutics by using the self-assembly of small molecules.…”

What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype

“…HS has emerging roles in oncogenesis of potential therapeutic value for human cancers as part of a complex HS signalling network [254]. Cell-surface HSPGs of the Sdc and Gpc families have key roles in the regulation of cell behaviour, cell signalling, and cell matrix interactions in normal and pathological tissues [255][256][257].…”