Abstract
The tetra-branched peptide NT4 selectively binds to different human cancer cells and tissues. NT4 specifically binds to sulfated glycosaminoglycans on cancer cell membranes. Since sulfated glycosaminoglycans are involved in cancer cell interaction with the extracellular matrix, we evaluated the effect of NT4 on cancer cell adhesion and migration. We demonstrated here that the branched peptide NT4 binds sulfated glycosaminoglycans with high affinity and with preferential binding to heparan sulfate. NT4 inhibits cancer cell adhesion and migration on different proteins, without modifying cancer cell morphology or their ability to produce protrusions, but dramatically affecting the directionality and polarity of cell movement. Results obtained by taking advantage of the selective targeting of glycosaminoglycans chains by NT4, provide insights into the role of heparan sulfate proteoglycans in cancer cell adhesion and migration and suggest a determinant role of sulfated glycosaminoglycans in the control of cancer cell directional migration.
Highlights
The tetra-branched peptide NT4 selectively binds to different human cancer cells and tissues
We demonstrated that the branched structure enables NT4 to bind membrane sulfated glycosaminoglycans (GAG), as well as different membrane endocytic receptors belonging to the low density lipoprotein receptor related (LRP) protein family such as LRP1 and LRP6, which are already known to be potentially druggable tumor markers involved in cancer biology[7]
Inhibition of NT4 binding to human pancreas adenocarcinoma PANC-1 cells by the same sulfated GAGs was essentially in line with their binding affinity, with complete inhibition of NT4 binding obtained with heparin, less inhibition obtained with heparan sulfate (HS) and no inhibition in the presence of the same concentration of chondroitin sulfate (CS)
Summary
The tetra-branched peptide NT4 selectively binds to different human cancer cells and tissues. In previous papers we reported the synthesis and biological activity of stable tetra-branched peptides containing the sequence of human neurotensin (NT4), coupled with different tracers or chemotherapy drugs. We found that the much higher binding of NT4 peptides than native neurotensin to cancer cell lines and human cancer surgical samples was generated by a switch in selectivity towards additional membrane receptors, which are selectively expressed by different human cancers. We demonstrated that the branched structure enables NT4 to bind membrane sulfated glycosaminoglycans (GAG), as well as different membrane endocytic receptors belonging to the low density lipoprotein receptor related (LRP) protein family such as LRP1 and LRP6, which are already known to be potentially druggable tumor markers involved in cancer biology[7]. Depending on the core protein, these can be divided into transmembrane (syndecan), GPI-anchored (glypican), and secreted (perlecan) heparan sulfate proteoglycans (HSPG)[9,10,11]
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