The Role of Cathelicidin LL-37 in Cancer Development

Abstract

LL-37 is a C-terminal peptide proteolytically released from 18 kDa human cathelicidin protein (hCAP18). Chronic infections, inflammation, tissue injury and tissue regeneration are all linked with neoplastic growth, and involve LL-37 antibacterial and immunomodulatory functions. Such a link points to the possible involvement of LL-37 peptide in carcinogenesis. An increasing amount of evidence suggests that LL-37 can have two different and contradictory effects—promotion or inhibition of tumor growth. The mechanisms are tissue-specific, complex, and depend mostly on the ability of LL-37 to act as a ligand for different membrane receptors whose expression varies on different cancer cells. Overexpression of LL-37 was found to promote development and progression of ovarian, lung and breast cancers, and to suppress tumorigenesis in colon and gastric cancer. This review explores and summarizes the current views on how LL-37 contributes to immunity, pathophysiology and cell signaling involved in malignant tumor growth.

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

“…Cathelicidins are antimicrobial peptides produced by mammals in response to various pathogenic microbes [1][2][3][4][5]. Human cathelicidin antimicrobial peptide (CAMP, hCAP-18) is the only member of the cathelicidin protein family in humans [1][2][3][4][5].…”

“…Human cathelicidin antimicrobial peptide (CAMP, hCAP-18) is the only member of the cathelicidin protein family in humans [1][2][3][4][5]. hCAP-18 (18kDa) is processed by proteolytic cleavage to bioactive cathelicidin LL-37 (37 amino acid residues with diLeucine at the N-terminus) by exposure to specific serine proteases like proteinase 3, kallikrein 5 and kallikrein 7 [1].…”

“…hCAP-18 (18kDa) is processed by proteolytic cleavage to bioactive cathelicidin LL-37 (37 amino acid residues with diLeucine at the N-terminus) by exposure to specific serine proteases like proteinase 3, kallikrein 5 and kallikrein 7 [1]. hCAP-18 is widely expressed in various epithelial cells Ovarian cancer LL-37 expression levels significantly increase in ovarian cancer tissues compared to the normal ovary tissues suggesting it might be a potential biomarker of ovarian cancer [2,35]. In ovarian cancer cells, recombinant LL-37 induces cell proliferation, cell invasion, chemotaxis, and matrix metalloproteinase (MMP) expression [35].…”

“…Lung cancer hCAP-18/LL-37 is expressed at elevated levels in human lung cancer cells at both the mRNA and protein levels [2,42,46,47]. Lung cancer cell lines that stably overexpress the hCAP-18 peptide also grow faster [46].…”

“…LL-37 activates the EGFR through MMP-mediated cleavage of membrane-anchored EGFR-ligands (Fig. 2B) [2,48]. On the other hand, IL-32 expression is distinctly altered in lung cancer cells and closely associated with increased lung cancer invasiveness, metastasis and poor prognosis [48,49].…”