Renovation as innovation: Repurposing human antibacterial peptide LL-37 for cancer therapy

Abstract

In many organisms, antimicrobial peptides (AMPs) display wide activities in innate host defense against microbial pathogens. Mammalian AMPs include the cathelicidin and defensin families. LL37 is the only one member of the cathelicidin family of host defense peptides expressed in humans. Since its discovery, it has become clear that they have pleiotropic effects. In addition to its antibacterial properties, many studies have shown that LL37 is also involved in a wide variety of biological activities, including tissue repair, inflammatory responses, hemotaxis, and chemokine induction. Moreover, recent studies suggest that LL37 exhibits the intricate and contradictory effects in promoting or inhibiting tumor growth. Indeed, an increasing amount of evidence suggests that human LL37 including its fragments and analogs shows anticancer effects on many kinds of cancer cell lines, although LL37 is also involved in cancer progression. Focusing on recent information, in this review, we explore and summarize how LL37 contributes to anticancer effect as well as discuss the strategies to enhance delivery of this peptide and selectivity for cancer cells.

Keywords: LL37; anticancer; antimicrobial peptides; cancer; cathelicidin (LL37); hCAP18.

FIGURE 1

Single cathelicidin gene called CAMP located on human chromosome 3p21.3 encodes hCAP18 (A), a schematic drawing of cDNA for the complete prepro-LL-37 (B), structure and cleavage sites of hCAP18 (C), and the amino acid sequence of the antibacterial peptide LL-37 (D). The human cathelicidin hCAP18 consists of a signal peptide (30 amino acids), N-terminal domain (103 amino acids), and C-terminal domain (37 amino acids). The C-terminal domain shows various activities as an active domain and is called LL-37.

FIGURE 2

Three-dimensional structure of human cathelicidin reveals a helix followed by a C-terminal tail. Note the four phenylalanine side chains lying on the concave surface of the peptide (F6, F5, F17, and F27) (A). Sequence of LL-37. S9 is marked (B). Stick view of the structure of LL-37 with hydrophobic and hydrophilic residues selectively labeled. In both views, hydrophobic amino acids are in purplish red (C). Therefore, it is evident that there is a discontinuation of the hydrophobic surface at S9 rather than the helices (Wang, 2008).

FIGURE 3

Helical wheel representation of LL-37, illustrating the amphipathic and cationic nature of LL-37. The residues are color coded: potentially negatively charged as red, potentially positively charged as dark blue, the hydrophobic residue is in yellow, the polar residues are coded as light blue, and the structurally special residues are coded as green. The helix diagram of the polypeptide was drawn with a Protein ORIGAMI (Reißer et al., 2018) software package. The arrow indicates the hydrophobic surface of the peptide.

FIGURE 4

Membrane-associated mechanism for the peptide. Picture illustrating the carpet model recommended for membrane permeation. The initial binding to the membrane interface is mediated by the electrostatic interaction. The peptide reaches the membrane in the form of a monomer or oligomer and then binds to the membrane surface (A). When the threshold concentration of peptide monomer is reached, the membrane is penetrated and forms instantaneous pores (B), which also leads to membrane disintegration (C).

FIGURE 5

Proposed non-membranolytic anticancer mechanism of human cathelicidin LL-37. Inhibition of proteasome activity induces the upregulation of BMP4, which subsequently activates BMP signaling. GPCR, G protein-coupled receptor; CXCR4, CXC chemokine receptor type 4; EndoG, endonuclease G; AIF, apoptosis-inducing factor; FPR1, formyl peptide receptor 1. BMP4, bone morphogenetic protein 4; BMPR, bone morphogenetic protein receptor.