Abstract
Initially characterized by its antimicrobial activities, LL-37 has also been shown to significantly contribute to tumor development. On breast cancer cell lines, LL-37 increases intracellular calcium via the TRPV2 channel and their migration via the activation of PI3K/AKT signaling. Its all-d enantiomer d-LL-37 induces similar effects, which excludes a protein-protein interaction of LL-37 in a classic ligand-receptor manner. Its net charge of +6 gave rise to the hypothesis that the peptide uses the negative charges of sulfoglycans or sialic acids to facilitate its attachment to the cell membrane and to induce its activities. Whereas several vegetal lectins, specifically attaching to sialylated or sulfated structures, blocked the activities of LL-37 on both calcium increase and cell migration, several sialidases had no effect. However, the competitive use of free sulfated glycoaminoglycans (GAGs) as chrondroitin and heparin, or treatment of the cell surface with chondroitinase and heparinase resulted in an activity loss of 50–100% for LL-37. Concordant results were obtained by blocking the synthesis of GAGs with 4-Methylumbelliferyl-β-d-xyloside, and by suppression of glycan sulfatation by sodium chlorate. Using a candidate approach by suppressing proteoglycan synthesis using RNA interference, syndecan-4 was shown to be required for the activities of LL-37 and its binding to the cell surface. This leads to the conclusion that syndecan-4, by means of sulfated GAGs, could act as a receptor for LL-37.
Highlights
The LL-37 peptide is released from the C-terminus of the Human Cathelicidin AntimicrobialProtein hCAP18
Since we assumed that the activities of LL-37 on the cancer cell might be reduced by blocking glycans on the cell surface, our first strategy was to mask negatively charge glycans such as sialic acid using lectins
The level of suppression varied among the lines: in presence of MAA I and II, migration of MDA-MB-231was suppressed by 50% and 30%, respectively, by 50% for both lectins for MDA-MB-435s, and 100% and 40%, respectively, for MCF7
Summary
The LL-37 peptide is released from the C-terminus of the Human Cathelicidin AntimicrobialProtein hCAP18. Increasing evidence has demonstrated a significant role in a variety of cancer where, depending on the cancer origin, both pro- and antitumorigenic effects have been reported [3,4]. These activities have been linked to the activation of multiple membrane-associated proteins, transmembrane receptors of different classes as well as ion channels [4,5]. Some of them have been suggested as being direct receptors for LL-37, their physical interaction remains to be characterized Their variety and structural diversity did not suggest a conventional receptor-ligand binding of LL-37 to these proteins as a common denominator for their activation.
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